WO2012030913A1 - Pyrazolylaminoquinazoline optiquement active, et ses compositions pharmaceutiques et méthodes d'utilisation - Google Patents

Pyrazolylaminoquinazoline optiquement active, et ses compositions pharmaceutiques et méthodes d'utilisation Download PDF

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WO2012030913A1
WO2012030913A1 PCT/US2011/049895 US2011049895W WO2012030913A1 WO 2012030913 A1 WO2012030913 A1 WO 2012030913A1 US 2011049895 W US2011049895 W US 2011049895W WO 2012030913 A1 WO2012030913 A1 WO 2012030913A1
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compound
methyl
pyrazol
quinazolin
fluorophenyl
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PCT/US2011/049895
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English (en)
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Mark W. Holladay
Eduardo Setti
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Ambit Biosciences Corporation
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Priority to ES11758009.2T priority Critical patent/ES2581840T3/es
Priority to JP2013527248A priority patent/JP5932794B2/ja
Priority to CA2809993A priority patent/CA2809993A1/fr
Priority to EP11758009.2A priority patent/EP2611795B1/fr
Priority to AU2011296074A priority patent/AU2011296074B2/en
Publication of WO2012030913A1 publication Critical patent/WO2012030913A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D15/00—Separating processes involving the treatment of liquids with solid sorbents; Apparatus therefor
    • B01D15/08—Selective adsorption, e.g. chromatography
    • B01D15/26—Selective adsorption, e.g. chromatography characterised by the separation mechanism
    • B01D15/38—Selective adsorption, e.g. chromatography characterised by the separation mechanism involving specific interaction not covered by one or more of groups B01D15/265 - B01D15/36
    • B01D15/3833—Chiral chromatography
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • an optically active pyrozolylaminoquinazaline and pharmaceutical compositions thereof. Also provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a JAK-mediated condition, disorder, or disease. Further provided herein is a method for treating, preventing, or ameliorating one or more symptoms of a proliferative disease, inflammatory disease, or renal disease.
  • the JAK kinase family is a cytoplasmic protein kinase family comprising the members JAK1, JAK2, JAK3, and TYK2.
  • Growth factor or cytokine receptors that recruit JAK kinases include the interferon receptors, interleukin receptors (receptors for the cytokines IL-2 to IL-7, IL-9 to IL-13, IL-15, IL-23), various hormone receptors
  • erythropoietin (Epo) receptor the thrombopoietin (Tpo) receptor, the leptin receptor, the insulin receptor, the prolactin (PRL) receptor, the granulocyte colony-stimulating factor (G- CSF) receptor, the growth hormone receptor, receptor protein tyrosine kinases (such as EGFR and PDGFR), and receptors for other growth factors (leukemia inhibitory factor (LIF), oncostatin M (OSM), IFNa/ ⁇ / ⁇ , granulocyte-macrophage colony-stimulating factor (GM- CSF), ciliary neurotrophic factor (CNTF), and cardiotrophin-1 (CT-1)).
  • LIF leukemia inhibitory factor
  • OSM oncostatin M
  • IFNa/ ⁇ / ⁇ granulocyte-macrophage colony-stimulating factor
  • GM- CSF granulocyte-macrophage colony-stimulating factor
  • CNTF
  • Phosphorylated receptors serve as docking sites for other SH-2 domain containing signaling molecules that interact with JAKs, such as the STAT family of transcription factors, Src family of kinases, MAP kinases, PI3 kinase, and protein tyrosine phosphatases (Rane and Reddy, Oncogene 2000, 19, 5662-5679).
  • the family of latent cytoplasmic transcription factors, STATs is the most well characterized downstream substrates for JAKs.
  • the STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to become phosphorylated by JAKs, which leads to their dimerization, release, and eventual translocation to the nucleus where they activate gene transcription.
  • the various members of STAT which have been identified thus far are STAT1 , STAT2, STAT3, STAT4, STAT5 (including STAT5a and STAT5b), and STAT6.
  • JAK kinases may play an important signaling role via such receptors, disorders of fat metabolism, growth disorders and disorders of the immune system are all potential therapeutic targets.
  • JAK kinases and JAK2 mutations are implicated in myeloproliferative disorders, cancers, including blood borne and solid tumors.
  • PV polycythemia vera
  • ET essential thrombocythemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML myelomonocytic leukemia
  • SM systemic mastocytosis
  • JAK may also serve as a target for prostate cancer, including androgen-resistant prostate cancer. See, Barton et al , Mol. Cane. Ther. 2004, 3, 1 1-20, Blume- Jensen et al , Nature 2001, 411, 355-356; Bromberg, J. Clin. Invest. 2002, 109, 1 139-1 142; and Rane, Oncogene 2000, 19, 5662-5679. JAK as a prominent mediator of the cytokine signaling pathway is considered to be a therapeutic target for inflammation and transplant rejections. See, Borie et al, Transplantation 2005, 79, 791-801; and Milici et al., Arthritis Research 2008, 10, 1-9.
  • optically active i?)-(4-fluorophenyl)(4-
  • a pharmaceutical composition comprising optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutical carrier, excipient or diluent.
  • optically active i?)-(4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or
  • a method of treating, preventing, or ameliorating one or more symptoms of a JAK-mediated condition, disorder, or disease in a subject comprising administering to the subject a therapeutically effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • optically active i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the growth of a cell comprising contacting the cell with optically active (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the growth of a cell in a subject comprising administering to the subject an effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • optically active i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of modulating the activity of a JAK kinase comprising contacting the JAK kinase with optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of modulating the activity of a JAK kinase in a subject comprising administering to the subject an effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of preventing, treating, or ameliorating one or more symptoms of an adenosine A 3 receptor-mediated condition, disorder, or disease in a subject comprising administering the subject a therapeutically effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of preventing, treating, or ameliorating one or more symptoms of glaucoma or ocular hypertension in a subject comprising administering the subject a therapeutically effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of modulating the activity of an adenosine A3 receptor comprising contacting the adenosine A 3 receptor with an effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of down regulating the activity of an adenosine A 3 receptor comprising contacting the adenosine A 3 receptor with an effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the chiral catalyst is [(5)-P-Phos RuCl 2 (S)-DAIPEN].
  • FIG. 1 depicts an LC chromatogram for the resolution of the two enantiomers of (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol by chiral high pressure liquid chromatography on a RegisCell chiral column eluting with 85: 15 hexane/isopropanol.
  • FIG. 1 depicts an LC chromatogram for the resolution of the two enantiomers of (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol by chiral high pressure liquid chromatography on a RegisCell chiral column eluting with 85: 15 hexane/isopropanol.
  • FIG. 3 depicts the X-ray crystal structure of optically active (R)-4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • FIG. 4 illustrates the results of the Kaplan Meier survival analysis for (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol compared to the racemate.
  • FIG. 5 illustrates the results of the Kaplan Meier survival analysis for (S)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol compared to the racemate.
  • FIG. 6 provides comparison of hydrogen uptake for hydrogenation of (4- fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone using 10% and 20%) DMSO (v/v) co-solvent with isopropyl alcohol at 60 °C, hydrogen pressure of 5 bar, and catalyst loading of 4000/1 S/C.
  • FIG. 7 provides hydrogen uptake with respect to time for hydrogenation of (4- fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone using 10% DMSO (v/v) co-solvent with isopropyl alcohol at 70 °C, hydrogen pressure of 5 bar, and catalyst loading of 4000/1 S/C.
  • FIG. 8 provides hydrogen uptake with respect to time for hydrogenation of (4- fluorophenyl)(4-(5-methyl-4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone using 10% DMSO (v/v) co-solvent with isopropyl alcohol at 70 °C, hydrogen pressure of 5 bar, and catalyst loading of 10,000/1 S/C.
  • tumor neoplasm
  • invasive neoplasm
  • cancer is meant to refer to a malignant neoplasm, which is characterized by uncontrolled cell proliferation where cells have lost their normal regulatory controls that would otherwise govern the rate of cell growth. These unregulated, dividing cells can spread throughout the body and invade normal tissues in a process referred to as "metastasis.”
  • subject refers to an animal, including, but not limited to, a primate
  • subject e.g., human
  • cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse e.g., cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • subject and patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • treat means to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • prevent are meant to include a method of delaying and/or precluding the onset of a disorder, disease, or condition, and/or its attendant symptoms; barring a subject from acquiring a disorder, disease, or condition; or reducing a subject's risk of acquiring a disorder, disease, or condition.
  • contacting or “contact” is meant to refer to bringing together of a therapeutic agent and cell or tissue such that a physiological and/or chemical effect takes place as a result of such contact. Contacting can take place in vitro, ex vivo, or in vivo.
  • a therapeutic agent is contacted with a cell in cell culture (in vitro) to determine the effect of the therapeutic agent on the cell.
  • the contacting of a therapeutic agent with a cell or tissue includes the administration of a therapeutic agent to a subject having the cell or tissue to be contacted.
  • terapéuticaally effective amount is meant to include the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • therapeutically effective amount also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • IC 50 or "EC 50” refers an amount, concentration, or dosage of a compound that is required for 50% inhibition of a maximal response in an assay that measures such response.
  • pharmaceutically acceptable carrier refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • the term “about” or “approximately” means an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term “about” or “approximately” means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term “about” or “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.
  • active ingredient and “active substance” refer to a compound, which is administered, alone or in combination with one or more pharmaceutically acceptable excipients, to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • active ingredient and active substance may be an optically active isomer of a compound described herein.
  • drug refers to a compound, or a pharmaceutical composition thereof, which is administered to a subject for treating, preventing, or ameliorating one or more symptoms of a condition, disorder, or disease.
  • solvate refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent, which is present in stoichiometric or non-stoichiometric amount.
  • Suitable solvents include, but are not limited to, water, methanol, ethanol, ft-propanol, isopropanol, and acetic acid.
  • the solvent is pharmaceutically acceptable. In one
  • the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a noncrystalline form.
  • the solvent is water
  • the solvate is a hydrate. Examples of hydrates include, but are not limited to, a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.
  • non-naturally occurring refers to materials which are found in nature and that has been structurally modified or synthesized by man.
  • JAK or "Just Another Kinase” refers to a Janus kinase or a variant thereof, including, but not limited to, Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2).
  • JAK variants include proteins substantially homologous to a native JAK, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g. , JAK derivatives, homologs and fragments), as compared to the amino acid sequence of a native JAK.
  • the amino acid sequence of a JAK variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native JAK.
  • JAK-mediated condition, disorder or disease and "a condition, disorder, or disease mediated by JAK” refer to a condition, disorder, or disease characterized by abnormal or dysregulated, e.g. , greater than normal, JAK activity.
  • Abnormal JAK functional activity might arise as the result of JAK overexpression in cells, expression of JAK in cells which normally do not express JAK, or dysregulation due to constitutive activation, caused, for example, by a mutation in JAK.
  • a JAK-mediated condition, disorder, or disease may be completely or partially mediated by inappropriate JAK activity.
  • a JAK- mediated condition, disorder, or disease is one in which modulation of a JAK activity results in some effect on the underlying condition, disorder, or disease, e.g., a JAK inhibitor results in some improvement in at least some of patients being treated.
  • A3AR refers to a native adenosine A 3 receptor or a variant thereof.
  • A3 AR variants include proteins substantially homologous to a native A3AR, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions or substitutions (e.g., A3AR derivatives, homologs and fragments), as compared to the amino acid sequence of a native A3 AR.
  • the amino acid sequence of a A3AR variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native A3AR.
  • an adenosine A 3 -mediated condition, disorder or disease and "a condition, disorder, or disease mediated by A3 AR” refer to a condition, disorder, or disease characterized by abnormal or dysregulated, e.g. , greater than normal, A3 AR activity.
  • Abnormal A3AR functional activity might arise as the result of A3AR overexpression in cells, expression of A3AR in cells which normally do not express A3AR, or dysregulation due to constitutively activation, caused, for example, by a mutation in A3 AR.
  • An A3 AR- mediated condition, disorder, or disease may be completely or partially mediated by inappropriate A3 AR activity.
  • an A3 AR-mediated condition, disorder, or disease is one in which modulation of A3 AR activity results in some effect on the underlying condition, disorder, or disease, e.g., an A3AR antagonist results in some improvement in at least some of patients being treated.
  • optically active and “enantiomerically active” refer to a collection of molecules, which has an enantiomeric excess of no less than about 10%, no less than about 20%, no less than about 30%, no less than about 40%, no less than about 50%, no less than about 60%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, no less than about 99.8%, or no less than about 99.9%.
  • enantiomerically active compound is no less than about 90%, no less than about 95%, no less than about 98%, or no less than about 99%.
  • the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the (+) and (-) are used to denote the optical rotation of the compound, that is, the direction in which a plane of polarized light is rotated by the optically active compound.
  • the (-) prefix indicates that the compound is levorotatory, that is, the compound rotates the plane of polarized light to the left or counterclockwise.
  • the (+) prefix indicates that the compound is dextrorotatory, that is, the compound rotates the plane of polarized light to the right or clockwise.
  • the sign of optical rotation, (+) and (-) is not related to the absolute configuration of the molecule, R and S.
  • optically pure and “enantiomerically pure” refer to a collection of molecules, which has an enantiomeric excess (ee) of no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, no less than about 99.8%, or no less than about 99.9%.
  • ee enantiomeric excess
  • the enantiomeric excess for an optically or enantiomerically pure compound is no less than about 90%, no less than about 95%, no less than about 98%, or no less than about 99%.
  • An enantiomeric excess of a compound can be determined by any standard methods used by one of ordinary skill in the art, including, but not limited to, chiroptical chromatography (gas chromatography, high- performance liquid chromatography, and thin-layer chromatography) using an optically active stationary phase, isotopic dilution, electrophoresis, calorimetry, polarimetry, NMR resolution methods with chiral derivatization, and NMR methods with a chiral solvating agent or chiral shift reagent.
  • substantially pure and substantially homogeneous mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by one of ordinary skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure such that further purification would not detectably alter the physical, chemical, biological, and/or pharmacological properties, such as enzymatic and biological activities, of the substance.
  • TLC thin layer chromatography
  • HPLC high performance liquid chromatography
  • GC gas chromatography
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • substantially pure or substantially homogeneous refers to a collection of molecules, wherein at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single stereoisomer of a compound, as determined by standard analytical methods.
  • isotopic variant refers to a compound that contains an unnatural proportion of an isotope at one or more of the atoms that constitute such compounds.
  • an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ⁇ H), deuterium ( 2 H), tritium ( 3 H), carbon-11 ( U C), carbon-12 ( 12 C), carbon-13 ( 13 C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), oxygen-16 ( 16 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), fiuorine-17 ( 17 F), fluorine-18 ( 18 F), phosphorus-31 ( 31 P), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-35 ( 35 S), sulfur-36 ( 36
  • an "isotopic variant" of a compound is in a stable form, that is, non-radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ⁇ H), deuterium ( 2 H), carbon-12 ( 12 C), carbon-13 ( 13 C), nitrogen- 14 ( 14 N), nitrogen-15 ( 15 N), oxygen-16 ( 16 0), oxygen-17 ( 17 0), oxygen-18 ( 18 0), fluorine-17 ( 17 F), phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), chlorine-35 ( 35 C1), chlorine-37 ( 37 C1), bromine-79 ( 79 Br), bromine-81 ( 81 Br), and iodine-127 ( I).
  • an "isotopic variant" of a compound is in an unstable form, that is, radioactive.
  • an "isotopic variant” of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, tritium ( 3 H), carbon-11 ( U C), carbon-14 ( 14 C), nitrogen-13 ( 13 N), oxygen-14 ( 14 0), oxygen-15 ( 15 0), fluorine-18 ( 18 F), phosphorus-32 ( 32 P), phosphorus-33 ( 33 P), sulfur-35 ( 35 S), chlorine-36 ( 36 C1), iodine-123 ( 123 I), iodine-125 ( 125 I), iodine-129 ( 129 I), and iodine-131 ( 131 I).
  • any hydrogen can be 2 H, for example, or any carbon can be 13 C, as example, or any nitrogen can be 15 N, as example, and any oxygen
  • an "isotopic variant" of a compound contains unnatural proportions of deuterium.
  • an isotopic variant thereof or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof has the same meaning as the phrase "an isotopic variant of the compound referenced therein; or a pharmaceutically acceptable salt, solvate, or prodrug of the compound referenced therein or an isotopic variant the compound referenced therein.”
  • optically active i?)-(4-fluorophenyl)(4-
  • the corresponding racemic mixture of the compound of Formula I has been identified as a JAK kinase inhibitor.
  • the corresponding racemic mixture of the compound of Formula I can be prepared according to U.S. Appl. No. 12/714,323, filed on February 26, 2010, now published as US 2010/0317659, the disclosure of which is incorporated by reference in its entirety.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol is substantially free from (S)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 10%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol- 3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 20%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5 -methyl- 1H- pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 30%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 40%.
  • the optically active (i?)-(4-fluorophenyl)(4- ((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 50%.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 60%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 70%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has an enantiomeric excess of no less than about 80%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 90%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol- 3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 91%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5 -methyl- ⁇ H- pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 92%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 93%.
  • the optically active (i?)-(4-fluorophenyl)(4- ((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 94%.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 95%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 96%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has an enantiomeric excess of no less than about 97%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 98%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol- 3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5 -methyl- ⁇ H- pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.1%.
  • the optically active (i?)-(4-fiuorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.2%.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.3%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.4%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has an enantiomeric excess of no less than about 99.5%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.6%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5 -methyl- ⁇ H- pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.7%.
  • the optically active (R)-(4-fluorophenyl)(4-((5- methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.8%.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has an enantiomeric excess of no less than about 99.9%.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a specific rotation of no greater than about -0.5, no greater than about -1, no greater than about -1.5, no greater than about -2, no greater than about -2.5, no greater than about -3, no greater than about -3.5, no greater than about -4, no greater than about -4.5, or no greater than about 5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -0.5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -1.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -1.5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -2.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -2.5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -3.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -3.5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -4.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -4.5.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol has a specific rotation of no greater than about -5.
  • the specific rotation of the compound of Formula I is determined according to Method 781 in USP XXXI (2003).
  • the specific rotation of the compound of Formula I is determined according to Method 781 in USP XXXI (2003) in methanol. In certain embodiments, the specific rotation of the compound of Formula I is determined according to Method 781 in USP XXXI (2003) at a temperature of about 22 °C.
  • the optically active (i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 80% by weight the (i?)-isomer and no greater than about 20% by weight (5)-isomer of (4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 90% by weight the (i?)-isomer and no greater than about 10% by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 91% by weight the (i?)-isomer and no greater than about 9% by weight (S)- isomer of (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 92% by weight the (i?)-isomer and no greater than about 8% by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 93% by weight the (i?)-isomer and no greater than about 7% by weight (S)- isomer of (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 94% by weight the (i?)-isomer and no greater than about 6% by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 95% by weight the (i?)-isomer and no greater than about 5% by weight (S)- isomer of (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 96% by weight the (i?)-isomer and no greater than about 4% by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 97% by weight the (i?)-isomer and no greater than about 3% by weight (S)- isomer of (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 98% by weight the (i?)-isomer and no greater than about 2% by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol contains no less than about 99% by weight the (i?)-isomer and no greater than about 1% by weight (S)- isomer of (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol contains no less than about 99.5% by weight the (R)- isomer and no greater than about 0.5% by weight (5)-isomer of (4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol contains no less than about 99.9% by weight the (i?)-isomer and no greater than about 0.1%) by weight (5)-isomer of (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol.
  • the optically active (i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol is substantially pure.
  • the optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol has a purity of at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 50% by weight. In certain embodiments, the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 70% by weight.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 80% by weight. In certain embodiments, the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 90% by weight.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 95% by weight. In certain embodiments, the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 98% by weight.
  • the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 99% by weight. In certain embodiments, the optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol has a purity of at least about 99.5% by weight.
  • the compound of Formula I is a modulator of a JAK kinase. In certain embodiments, the compound of Formula I is a modulator of a JAKl kinase. In certain embodiments, the compound of Formula I is a modulator of a JAK2 kinase. In certain embodiments, the compound of Formula I is a modulator of a JAK3 kinase. In certain embodiments, the compound of Formula I is a modulator of a TYK2 kinase.
  • the compound of Formula I is a modulator selective for a JAK2 kinase. In certain embodiments, the compound of Formula I is a modulator selective for a JAK2 kinase over a JAK3 kinase. In certain embodiments, the compound of Formula I binds to a JAK3 kinase at a dissociation constant (K d ) of at least about 2-fold, at least about 3 -fold, about 5 -fold, about 10-fold, about 20-fold, about 25 -fold, about 50-fold, about 75-fold, or about 100-fold higher than to a JAK2 kinase.
  • K d dissociation constant
  • the compound of Formula I is a modulator selective for a JAK2 kinase over a JAKl kinase.
  • the compound of Formula I binds to a JAKl kinase at a dissociation constant (K d ) of at least about 2-fold, at least about 3-fold, about 5-fold, about 10-fold, about 20-fold, about 25-fold, or about 50-fold higher than to a JAK2 kinase.
  • K d dissociation constant
  • the compound of Formula I is a modulator selective for a JAK2 kinase over a TYK2 kinase.
  • the compound of Formula I binds to a TYK2 kinase at a dissociation constant (K d ) of at least about 2-fold, at least about 3 -fold, about 5 -fold, about 10-fold, about 20-fold, about 25-fold, or about 50-fold higher than to a JAK2 kinase.
  • K d dissociation constant
  • the compound of Formula I is an inhibitor of a JAK kinase. In certain embodiments, the compound of Formula I is an inhibitor of a JAKl kinase. In certain embodiments, the compound of Formula I is an inhibitor of a JAK2 kinase. In certain embodiments, the compound of Formula I is an inhibitor of a JAK3 kinase. In certain embodiments, the compound of Formula I is an inhibitor of a TYK2 kinase.
  • the compound of Formula I is an inhibitor selective for a JAK2 kinase. In certain embodiments, the compound of Formula I is an inhibitor selective for a JAK2 kinase over a JAK3 kinase. In certain embodiments, the compound of Formula I inhibits a JAK3 kinase at an inhibitory constant ( ⁇ ;) of at least about 2-fold, at least about 3 -fold, about 5 -fold, about 10-fold, about 20-fold, about 25 -fold, about 50-fold, about 75-fold, or about 100-fold higher than a JAK2 kinase.
  • ⁇ inhibitory constant
  • the compound of Formula I is an inhibitor selective for a JAK2 kinase over a JAK1 kinase. In certain embodiments, the compound of Formula I inhibits a JAK1 kinase at an inhibitory constant ( ⁇ ;) of at least about 2-fold, at least about 3-fold, about 5-fold, about 10-fold, about 20-fold, about 25-fold, or about 50-fold higher than to a JAK2 kinase. In certain
  • the compound of Formula I is an inhibitor selective for a JAK2 kinase over a TYK2 kinase.
  • the compound of Formula I inhibits a TYK2 kinase at an inhibitory constant ( ⁇ ;) of at least about 2-fold, at least about 3 -fold, about 5 -fold, about 10-fold, about 20-fold, about 25-fold, or about 50-fold higher than to a JAK2 kinase.
  • optically active i?)-(4-fluorophenyl)(4-
  • Isotopic enrichment (for example, deuteration) of therapeutic agents to improve pharmacokinetics ("PK"), pharmacodynamics ("PD”), and/or toxicity profiles has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et. al, Food Cosmet. Toxicol., 1982, 20, 393; Lijinsky et. al., J. Nat.
  • Isotopic enrichment of a drug can be used, for example, (1) to reduce or eliminate undesirable metabolites, (2) to increase the half-life of the parent drug, (3) to decrease the number of doses needed to achieve a desired effect, (4) to decrease the amount of a dose necessary to achieve a desired effect, (5) to increase the formation of active metabolites, if any are formed, and/or (6) to decrease the production of deleterious metabolites in specific tissues and/or to create a more effective drug and/or a safer drug for combination therapy, whether the combination therapy is intentional or not.
  • Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (-)-(lR)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glu
  • (i?)-(4-fluorophenyl)(4-(5-methyl- lH-pyrazol-3-ylamino)quinazolin-2-yl)methanol is a hydrochloride salt, or pharmaceutically acceptable solvate or hydrate thereof.
  • the pharmaceutically acceptable salt of optically active (i?)-(4-fluorophenyl)(4- (5-methyl-lH-pyrazol-3-ylamino)quinazolin-2-yl)methanol is a hydrobromide salt, or pharmaceutically acceptable solvate or hydrate thereof.
  • the pharmaceutically acceptable salt of optically active (R)-(4-fluorophenyl)(4-(5-methyl-lH- pyrazol-3-ylamino)quinazolin-2-yl)methanol is a camphor sulfonic acid salt, or pharmaceutically acceptable solvate or hydrate thereof.
  • the pharmaceutically acceptable salt of optically active (i?)-(4-fluorophenyl)(4-(5-methyl-lH- pyrazol-3-ylamino)quinazolin-2-yl)methanol is an i?-camphor sulfonic acid salt, or pharmaceutically acceptable solvate or hydrate thereof.
  • the pharmaceutically acceptable salt of optically active (i?)-(4-fluorophenyl)(4-(5-methyl-lH- pyrazol-3-ylamino)quinazolin-2-yl)methanol is an S-camphor sulfonic acid salt, or pharmaceutically acceptable solvate or hydrate thereof.
  • optically active i?)-(4-fluorophenyl)(4-(5-methyl-lH-pyrazol-3- ylamino)quinazolin-2-yl)methanol.
  • a pharmaceutically acceptable prodrug of optically active (i?)-(4-fluorophenyl)(4-(5-methyl-lH-pyrazol-3- ylamino)quinazolin-2-yl)methanol is provided herein.
  • a prodrug is a functional derivative of a parent compound, e.g., the compound of Formula I, and is readily convertible into the parent compound in vivo.
  • Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not.
  • the prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound.
  • a prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See, Harper, Progress in Drug Research 1962, 4, 221-294;
  • the compound provided herein is intended to encompass all possible structural isomers, unless a particular structural isomer is specified. Where structural isomers are interconvertible, the compound may exist as a single tautomer or a mixture of tautomers. This can take the form of proton tautomerism in the compound that contains, for example, an imino, keto, or oxime group; or so-called valence tautomerism in the compound that contain an aromatic moiety. It follows that a single compound may exhibit more than one type of isomerism.
  • the compound of Formula I provided herein can be prepared, isolated, or obtained by any method known to one of skill in the art, including, but not limited to, synthesis from a suitable optically pure precursor, asymmetric synthesis from an achiral starting material, or resolution of a racemic or enantiomeric mixture, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation.
  • a method for preparation of the compound of Formula I which comprises resolving racemic (4-fluorophenyl)(4-(5-methyl- lH-pyrazol-3-ylamino)quinazolin-2-yl)methanol with chiral chromatography.
  • the two individual enantiomers are separated using a chiral column, wherein the stationary phase is silica gel coated with a chiral selector such as tris-(3,5-dimethylphenyl)carbamoyl cellulose.
  • a method for preparation of the compound of Formula I comprising the step of reducing achiral ketone 1 with hydrogen in the present of a chiral catalyst.
  • ketone 1 is reduced to predominantly a single enantiomeric product with a chiral reducing system of "type A" or "type B,” wherein type A and type B differ from each other solely by having chiral auxiliaries of opposite chiralities.
  • the chiral catalyst is [(5)-P-Phos RuCl 2 (S)-DAIPEN].
  • the reduction of achiral ketone 1 in presence of a chiral catalyst is carried out in isopropyl alcohol as a solvent. In certain embodiments, the reduction of achiral ketone 1 in presence of a chiral catalyst is carried out in isopropyl alcohol and water mixture as a solvent. In certain embodiments, isopropyl alcohol and water are used in a ratio of 1 : 1 , 8: 1 or 9: 1. In one embodiment, DMSO is used as a cosolvent in the reaction. In one embodiment, DMSO is used in 10, 20 or 30% based on the total amount of isopropyl alcohol and water mixture.
  • isopropyl alcohol, DMSO and water are used in a ratio of 1 : 1 : 1 , 4:4:0.5, 8: 1 : 1 , 47:47:6, 41 :58: 1 , 44:50:6, or 18:79:3.
  • isopropyl alcohol, DMSO and water are used in a ratio of 41 :58: 1.
  • isopropyl alcohol, and DMSO are used in a ratio of 1 : 1.
  • the reduction is carried out in presence of a base, such as potassium hydroxide, potassium tert butoxide and others.
  • the base is used in 2-15 Mol%, in one embodiment, 2 Mol%, 5 Mol%, 10 Mol%, 12.5 Mol% or 15 Mol%.
  • the reduction is carried out at a temperature of 40-80 °C, in one embodiment, 40 °C, 50 °C, 60 °C, 70 °C or 80 °C.
  • the reduction is carried out at a temperature of 70 °C.
  • the reduction is carried out at a pressure of 4 bar to 30 bar, in one embodiment, 4, 5, 10, 15, 20, 25 or 30 bar.
  • the reduction is carried out at a pressure of 4 bar.
  • the catalyst loading in the reaction is 100/1, 250/1, 500/1, 1000/1, 2000/1, 3000/1, 4000/1, 5000/1, 7000/1,
  • the catalyst loading in the reaction is 2000/1 or 4000/1.
  • a method for preparation of the compound of Formula I which comprises the step of reducing achiral ketone 1 with a ketoreductase (e.g., alcohol dehydrogenase).
  • a ketoreductase e.g., alcohol dehydrogenase
  • a method for preparation of the compound of Formula I comprising the step of reducing achiral ketone 1 with a reducing reagent (e.g. , borane or borohydride reagents) in the presence of a chiral catalyst.
  • a reducing reagent e.g. , borane or borohydride reagents
  • the reducing agent is borane or a borohydride reagent.
  • the chiral catalyst is a chiral oxazaborolidine. See, Cory et al., Tetrahedron Letters 1996, 37, 5675; and Cho, Chem. Soc. Rev. 2009, 38, 443.
  • a method for preparation of the compound of Formula I comprising the step of reducing achiral ketone 1 via asymmetric hydrosilylation. See, U.S. Appl. Pub. No. 2008/0269490, the disclosure of which is incorporated herein by reference in its entirety.
  • a method for preparation of the compound of Formula I comprising the step of reducing achiral ketone 1 via transfer hydrogenation catalyzed by an iridium complex. See, Malacea et al., Coordination
  • ketone 1 can be prepared according to the methods described in U.S. Appl. No. 12/714,323, filed on February 26, 2010, the disclosure of which is incorporated herein by reference in its entirety.
  • a pharmaceutical composition comprising optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
  • a pharmaceutical composition comprising optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and PEG 400 and water.
  • the weight ratio of PEG 400 versus water is 3: 1.
  • the pharmaceutical composition is for intravenous administration.
  • Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. For example, oral dosage forms such as tablets may contain excipients not suited for use in parenteral dosage forms. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form. For example, the
  • lactose-free compositions contain little, if any, lactose, or other mono- or di-saccharides.
  • lactose-free compositions comprise an active ingredient provided herein, a binder/filler, and a lubricant.
  • lactose-free dosage forms comprise an active ingredient, microcrystalline cellulose, pre- gelatinized starch, and magnesium stearate.
  • optically active compound of Formula I provided herein may be administered alone, or in combination with one or more other compounds provided herein.
  • the pharmaceutical compositions that comprise the active compound of Formula I provided herein can be formulated in various dosage forms for oral, parenteral, and topical
  • compositions can also be formulated as modified release dosage forms, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • modified release dosage forms including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated-, fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • the pharmaceutical compositions are provided in a dosage form for oral administration, which comprise optically active (i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
  • optically active i?)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
  • compositions are provided in a dosage form for parenteral administration, which comprise optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
  • the pharmaceutical compositions are provided in a dosage form for topical administration, which comprise optically active (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and one or more pharmaceutically acceptable vehicles, carriers, diluents, or excipients.
  • the topical administration is nasal, respiratory, or pulmonary administration.
  • compositions provided herein can be provided in a unit- dosage form or multiple-dosage form.
  • a unit-dosage form refers to a physically discrete unit suitable for administration to a human and animal subject, and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of an active ingredient(s) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of a unit- dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit-dosage form may be administered in fractions or multiples thereof.
  • a multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage forms.
  • Examples of a multiple-dosage form include a vial, bottle of tablets or capsules, or bottle of pints or gallons.
  • compositions provided herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • the pharmaceutical compositions provided herein each contain from about 0.1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the optically active compound of Formula I provided herein.
  • the pharmaceutical dosage unit forms provided herein contain from about 1 mg to about 2,000 mg, from about 10 mg to about 1,000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of the optically active compound of Formula I provided herein per dosage unit form.
  • the pharmaceutical dosage unit forms contain about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, about 250 mg, about 500 mg, about 1,000 mg, or about 2,000 mg of the optically active compound of Formula I provided herein.
  • the pharmaceutical compositions provided herein are co-formulated with one or more other active ingredients, which do not impair the desired therapeutic action, or with substances that supplement the desired action.
  • oral administration can be provided in solid, semisolid, or liquid dosage forms.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • pharmaceutically acceptable carriers or excipients including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, flavoring agents, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and sources of carbon dioxide.
  • Binders or granulators impart cohesiveness to a tablet to ensure the tablet remaining intact after compression.
  • Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pre-gelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as acacia, alginic acid, alginates, extract of Irish moss, panwar gum, ghatti gum, mucilage of isabgol husks, carboxymethylcellulose,
  • methylcellulose methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabogalactan, powdered tragacanth, and guar gum; celluloses, such as ethyl cellulose, cellulose acetate,
  • carboxymethyl cellulose calcium sodium carboxymethyl cellulose, methyl cellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101 , AVICEL-PH-103, AVICEL RC-581 , AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof.
  • Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre- gelatinized starch, and mixtures thereof. The amount of a binder or filler in the
  • compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the binder or filler may be present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.
  • Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar.
  • Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol when present in sufficient quantity, can impart properties to some compressed tablets that permit disintegration in the mouth by chewing. Such compressed tablets can be used as chewable tablets.
  • the amount of a diluent in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • Suitable disintegrants include, but are not limited to, agar; bentonite;
  • celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked celluloses, such as croscarmellose; cross-linked polymers, such as crospovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches, such as corn starch, potato starch, tapioca starch, and pre-gelatinized starch; clays; aligns; and mixtures thereof.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • the amount of a disintegrant in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to those of ordinary skill in the art.
  • compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.
  • Suitable lubricants include, but are not limited to, calcium stearate;
  • magnesium stearate mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laureate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL ® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL ® (Cabot Co. of Boston, MA); and mixtures thereof.
  • the pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of a lubricant.
  • Suitable glidants include, but are not limited to, colloidal silicon dioxide,
  • Suitable coloring agents include, but are not limited to, any of the approved, certified, water soluble FD&C dyes, and water insoluble FD&C dyes suspended on alumina hydrate, and color lakes and mixtures thereof.
  • a color lake is the combination by adsorption of a water-soluble dye to a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye.
  • Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants, such as fruits, and synthetic blends of compounds which produce a pleasant taste sensation, such as peppermint and methyl salicylate.
  • Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners, such as saccharin and aspartame.
  • Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate
  • suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, Veegum, acacia, sodium carbomethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic add, sodium benzoate and alcohol.
  • Suitable wetting agents include, but are not limited to, propylene glycol
  • Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup.
  • Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.
  • Suitable organic acids include, but are not limited to, citric and tartaric acid.
  • Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.
  • compositions provided herein for oral administration can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets.
  • Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
  • Enteric-coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates.
  • Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which may be beneficial in covering up objectionable tastes or odors and in protecting the tablets from oxidation.
  • Film-coated tablets are compressed tablets that are covered with a thin layer or film of a water-soluble material.
  • Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating.
  • Multiple compressed tablets are compressed tablets made by more than one compression cycle, including layered tablets, and press-coated or dry-coated tablets.
  • the tablet dosage forms can be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
  • the pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate.
  • the hard gelatin capsule also known as the dry- filled capsule (DFC)
  • DFC dry- filled capsule
  • the soft elastic capsule is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol.
  • the soft gelatin shells may contain a preservative to prevent the growth of microorganisms.
  • Suitable preservatives are those as described herein, including methyl- and propyl-parabens, and sorbic acid.
  • the liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule.
  • Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545.
  • the capsules may also be coated as known by those of skill in the art in order to modify or sustain dissolution of the active ingredient.
  • compositions provided herein for oral administration can be provided in liquid and semisolid dosage forms, including emulsions, solutions,
  • An emulsion is a two-phase system, in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in- water or water-in-oil.
  • Emulsions may include a pharmaceutically acceptable non-aqueous liquid or solvent, emulsifying agent, and preservative.
  • Suspensions may include a pharmaceutically acceptable suspending agent and preservative.
  • Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol.
  • Elixirs are clear, sweetened, and hydroalcoholic solutions.
  • Syrups are concentrated aqueous solutions of a sugar, for example, sucrose, and may also contain a preservative.
  • a solution in a polyethylene glycol may be diluted with a sufficient quantity of a
  • liquid carrier e.g., water
  • liquid and semisolid dosage forms include, but are not limited to, those containing the active ingredient(s) provided herein, and a dialkylated mono- or poly- alkylene glycol, including, 1 ,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,
  • polyethylene glycol-750-dimethyl ether wherein 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol.
  • These formulations can further comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
  • antioxidants such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid,
  • compositions provided herein for oral administration can be also provided in the forms of liposomes, micelles, microspheres, or nanosystems.
  • Micellar dosage forms can be prepared as described in U.S. Pat. No. 6,350,458.
  • compositions provided herein for oral administration can be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form.
  • Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents.
  • Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
  • Coloring and flavoring agents can be used in all of the above dosage forms.
  • compositions provided herein for oral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein can be administered parenterally by injection, infusion, or implantation, for local or systemic administration.
  • Parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular,
  • compositions provided herein for parenteral are provided herein for parenteral.
  • administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes,
  • microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science ⁇ see, Remington: The Science and Practice of Pharmacy, supra).
  • compositions intended for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.
  • aqueous vehicles water-miscible vehicles
  • non-aqueous vehicles non-aqueous vehicles
  • antimicrobial agents or preservatives against the growth of microorganisms stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emuls
  • Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringers injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringers injection.
  • Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil, and palm seed oil.
  • Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol ⁇ e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N- methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.
  • Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p- hydroxybenzoates, thimerosal, benzalkonium chloride (e.g. , benzethonium chloride), methyl- and propyl-parabens, and sorbic acid.
  • Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin, and dextrose.
  • Suitable buffering agents include, but are not limited to, phosphate and citrate.
  • Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite.
  • Suitable local anesthetics include, but are not limited to, procaine hydrochloride.
  • Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcelluose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.
  • Suitable emulsifying agents are those described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate.
  • Suitable sequestering or chelating agents include, but are not limited to EDTA.
  • Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid.
  • Suitable complexing agents include, but are not limited to, cyclodextrins, including a-cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, sulfobutylether-P-cyclodextrin, and sulfobutylether
  • the multiple dosage parenteral formulations must contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. All parenteral formulations must be sterile, as known and practiced in the art.
  • the pharmaceutical compositions for parenteral administration are provided as ready-to-use sterile solutions.
  • the pharmaceutical compositions are provided as sterile dry soluble products, including lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile suspensions.
  • the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle prior to use.
  • the pharmaceutical compositions are provided as ready-to-use sterile emulsions.
  • the pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or modified release dosage forms, including delayed-, sustained, pulsed-, controlled, targeted-, and programmed-release forms.
  • compositions provided herein for parenteral are provided herein for parenteral.
  • administration can be formulated as a suspension, solid, semi-solid, or thixotropic liquid, for administration as an implanted depot.
  • the pharmaceutical compositions provided herein are dispersed in a solid inner matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical compositions diffuse through.
  • Suitable inner matrixes include, but are not limited to,
  • polyvinylchloride plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers, such as hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.
  • Suitable outer polymeric membranes include but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethyl siloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride, vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene
  • compositions provided herein can be administered topically to the skin, orifices, or mucosa.
  • topical administration includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory, pulmonary, and rectal administration.
  • compositions provided herein can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and dermal patches.
  • the topical formulation of the pharmaceutical compositions provided herein can also comprise liposomes, micelles, microspheres, nanosystems, and mixtures thereof.
  • Pharmaceutically acceptable carriers and excipients suitable for use in the topical formulations provided herein include, but are not limited to, aqueous vehicles, water- miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.
  • compositions can also be administered topically by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECTTM (Chiron Corp., Emeryville, CA), and BIOJECTTM (Bioject Medical Technologies Inc., Tualatin, OR).
  • electroporation iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection
  • BIOJECTTM Bioject Medical Technologies Inc., Tualatin, OR
  • Suitable ointment vehicles include oleaginous or hydrocarbon vehicles, including lard, benzoinated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorption vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emulsion vehicles, either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These vehicles are emollient but generally require addition
  • Suitable cream base can be oil-in-water or water-in-oil.
  • Suitable cream vehicles may be water-washable, and contain an oil phase, an emulsifier, and an aqueous phase.
  • the oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol.
  • the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.
  • Gels are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL ® ; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin.
  • dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.
  • compositions provided herein can be administered rectally, urethrally, vaginally, or perivaginally in the forms of suppositories, pessaries, bougies, poultices or cataplasm, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas.
  • These dosage forms can be manufactured using conventional processes as described in Remington: The Science and Practice of Pharmacy, supra.
  • Rectal, urethral, and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(s) inside the orifices.
  • Pharmaceutically acceptable carriers utilized in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which produce a melting point in the proximity of body temperature, when formulated with the pharmaceutical compositions provided herein; and antioxidants as described herein, including bisulfite and sodium metabisulfite.
  • Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di- and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of the various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compressing or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.
  • compositions provided herein can be administered ophthalmically in the forms of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solutions, gels, ocular inserts, and implants.
  • the pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract.
  • the pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • atomizer such as an atomizer using electrohydrodynamics to produce a fine mist, or nebulizer
  • a suitable propellant such as 1,1,1,2- tetrafluoroethane or 1,1, 1,2,3, 3,3-heptafluoropropane.
  • the pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and nasal drops.
  • Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer can be formulated to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilizing, or extending release of the active ingredient provided herein; a propellant as solvent; and/or a surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less.
  • Particles of such sizes can be prepared using a comminuting method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules, blisters, and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mix of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier, such as /- leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate.
  • Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.
  • the pharmaceutical compositions provided herein for inhaled/intranasal administration can further comprise a suitable flavor, such as menthol and levomenthol; and/or sweeteners, such as saccharin and saccharin sodium.
  • compositions provided herein for topical administration can be formulated to be immediate release or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted, and programmed release.
  • modified release dosage form refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route.
  • Modified release dosage forms include, but are not limited to, delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms.
  • compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof.
  • the release rate of the active ingredient(s) can also be modified by varying the particle sizes and polymorphorism of the active ingredient(s).
  • modified release examples include, but are not limited to, those described in U.S. Pat. Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;
  • compositions provided herein in a modified release dosage form can be fabricated using a matrix controlled release device known to those skilled in the art. See, Takada et al. in Encyclopedia of Controlled Drug Delivery; Mathiowitz Ed.; Wiley: 1999; Vol. 2.
  • the pharmaceutical compositions provided herein in a modified release dosage form is formulated using an erodible matrix device, which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • an erodible matrix device which is water- swellable, erodible, or soluble polymers, including, but not limited to, synthetic polymers, and naturally occurring polymers and derivatives, such as polysaccharides and proteins.
  • Materials useful in forming an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; gum agar, gum arabic, gum karaya, locust bean gum, gum tragacanth, carrageenans, gum ghatti, guar gum, xanthan gum, and scleroglucan;
  • starches such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosics, such as ethyl cellulose (EC), methylethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethyl cellulose (EHEC);
  • EC ethyl cellulose
  • MEC carboxymethyl cellulose
  • CMC carboxy
  • polyvinyl pyrrolidone polyvinyl alcohol
  • polyvinyl acetate polyvinyl acetate
  • glycerol fatty acid esters polyvinyl pyrrolidone
  • polyacrylamide polyacrylic acid
  • the pharmaceutical compositions provided herein are formulated with a non-erodible matrix device.
  • the active ingredient(s) is dissolved or dispersed in an inert matrix and is released primarily by diffusion through the inert matrix once administered.
  • Materials suitable for use as a non-erodible matrix device include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate
  • insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethylmethacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinylchloride, methyl acrylate-methyl methacrylate copolymers, ethylene- vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate
  • copolymers vinyl chloride copolymers with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubbers, epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, ethylene/vinyl acetate/vinyl alcohol terpolymer, ethylene/vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubbers, polydimethylsiloxanes, and silicone carbonate copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds, such as carnauba wax, microcrystalline wax, and triglycerides.
  • the desired release kinetics can be controlled, for example, via the polymer type employed, the polymer viscosity, the particle sizes of the polymer and/or the active ingredient(s), the ratio of the active ingredient(s) versus the polymer, and other excipients or carriers in the compositions.
  • compositions provided herein in a modified release dosage form can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt-granulation followed by compression.
  • compositions provided herein in a modified release dosage form can be fabricated using an osmotic controlled release device, including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • an osmotic controlled release device including, but not limited to, one-chamber system, two-chamber system, asymmetric membrane technology (AMT), and extruding core system (ECS).
  • AMT asymmetric membrane technology
  • ECS extruding core system
  • such devices have at least two components: (a) a core which contains an active ingredient; and (b) a semipermeable membrane with at least one delivery port, which encapsulates the core.
  • the semipermeable membrane controls the influx of water to the core from an aqueous environment of use so as to cause drug release by extrusion through the delivery port(s).
  • the core of the osmotic device optionally includes an osmotic agent, which creates a driving force for transport of water from the environment of use into the core of the device.
  • osmotic agents water-swellable hydrophilic polymers, which are also referred to as “osmopolymers” and “hydrogels.”
  • Suitable water-swellable hydrophilic polymers as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid,
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl alcohol
  • PVA/PVP copolymers PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium
  • croscarmellose hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl, cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.
  • HEC hydroxyethyl cellulose
  • HPMC hydroxypropyl cellulose
  • HPMC hydroxypropyl methyl cellulose
  • CMC carboxymethyl cellulose
  • CEC carboxyethyl
  • sodium alginate sodium alginate
  • polycarbophil gelatin
  • gelatin xanthan gum
  • sodium starch glycolate sodium alginate
  • the other class of osmotic agents is osmogens, which are capable of imbibing water to affect an osmotic pressure gradient across the barrier of the surrounding coating.
  • Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphates, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic
  • Osmotic agents of different dissolution rates can be employed to influence how rapidly the active ingredient(s) is initially delivered from the dosage form.
  • amorphous sugars such as MANNOGEM TM EZ (SPI Pharma, Lewes, DE) can be used to provide faster delivery during the first couple of hours to promptly produce the desired therapeutic effect, and gradually and continually release of the remaining amount to maintain the desired level of therapeutic or prophylactic effect over an extended period of time.
  • the active ingredient(s) is released at such a rate to replace the amount of the active ingredient metabolized and excreted.
  • the core can also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to promote stability or processing.
  • Materials useful in forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pHs, or are susceptible to being rendered water-insoluble by chemical alteration, such as crosslinking.
  • Suitable polymers useful in forming the coating include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluene sulfonate, agar acetate, amylose triacetate, beta glucan acetate, beta glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinylacetate, EC, PEG, PPG, PEG/PPG copo
  • Semipermeable membrane can also be a hydrophobic microporous membrane, wherein the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as disclosed in U.S. Pat. No. 5,798,119.
  • Such hydrophobic but water-vapor permeable membrane are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.
  • the delivery port(s) on the semipermeable membrane can be formed post- coating by mechanical or laser drilling. Delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of the membrane over an indentation in the core. In addition, delivery ports can be formed during coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Pat. Nos.
  • the total amount of the active ingredient(s) released and the release rate can substantially by modulated via the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and position of the delivery ports.
  • compositions in an osmotic controlled-release dosage form can further comprise additional conventional excipients or carriers as described herein to promote performance or processing of the formulation.
  • the osmotic controlled-release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J Controlled Release 1995, 35, 1-21; Verma et al, Drug Development and Industrial Pharmacy 2000, 26, 695-708; and Verma et al., J. Controlled Release 2002, 79, 7-27.
  • the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage form, which comprises an asymmetric osmotic membrane that coats a core comprising the active ingredient(s) and other pharmaceutically acceptable excipients or carriers.
  • AMT controlled-release dosage form can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and a dip-coating method.
  • the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage form, which comprises an osmotic membrane that coats a core comprising the active ingredient(s), a hydroxylethyl cellulose, and other pharmaceutically acceptable excipients or carriers.
  • the pharmaceutical compositions provided herein in a modified release dosage form can be fabricated as a multiparticulate controlled release device, which comprises a multiplicity of particles, granules, or pellets, ranging from about 10 ⁇ to about 3 mm, about 50 ⁇ to about 2.5 mm, or from about 100 ⁇ to about 1 mm in diameter.
  • Such multiparticulates can be made by the processes known to those skilled in the art, including wet-and dry-granulation, extrusion/spheronization, roller-compaction, melt-congealing, and by spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; Ghebre- Sellassie Ed.; Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology; Ghebre- Sellassie Ed.; Marcel Dekker: 1989.
  • excipients or carriers as described herein can be blended with the pharmaceutical compositions to aid in processing and forming the multiparticulates.
  • the resulting particles can themselves constitute the multiparticulate device or can be coated by various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers.
  • the multiparticulates can be further processed as a capsule or a tablet.
  • compositions provided herein can also be formulated to be targeted to a particular tissue, receptor, or other area of the body of the subject to be treated, including liposome-, resealed erythrocyte-, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in U.S. Pat. Nos. 5,709,874; 5,759,542;
  • a method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease, inflammatory disease, or renal disease in a subject comprising administering to the subject a therapeutically effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating a proliferative disease, inflammatory disease, or renal disease in a subject comprising administering to the subject a therapeutically effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the proliferative disease is a myeloproliferative disorder, including, but not limited to, polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), and idiopathic
  • PCV polycythemia vera
  • E essential thrombocythemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • SM systemic mastocytosis
  • the proliferative disease is leukemia, including, but not limited to, myeloid leukemia, chronic myeloid leukemia (CML), imatinib- resistant CMLs, acute myeloid leukemia (AML), and acute megakaryoblastic leukemia (AMKL).
  • the proliferative disease is a lymphoproliferative disease, including, but not limited to, myeloma.
  • the proliferative disease is cancer, including, but not limited to, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, and renal carcinoma.
  • the inflammatory disease or disorder includes, but is not limited to, immune dysfunction, immunodeficiency, immunomodulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
  • renal disease is diabetic neuropathy.
  • a method of treating, preventing, or ameliorating one or more symptoms of a JAK-mediated condition, disorder, or disease, in a subject comprising administering to the subject a therapeutically effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of treating, preventing, or ameliorating a JAK-mediated condition, disorder, or disease, in a subject comprising administering to the subject a therapeutically effective amount of optically active ( ⁇ S)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • optically active ( ⁇ S)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the JAK-mediated condition, disorder, or disease is a myeloproliferative disorder, including, but not limited to, polycythemia vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM), and idiopathic myelofibrosis (IMF).
  • PCV polycythemia vera
  • E essential thrombocythemia
  • PMF primary myelofibrosis
  • CEL chronic eosinophilic leukemia
  • CMML chronic myelomonocytic leukemia
  • SM systemic mastocytosis
  • IMF idiopathic myelofibrosis
  • the JAK-mediated condition, disorder, or disease is leukemia, including, but not limited to, myeloid leukemia, chronic myeloid leukemia (CML), imatinib-resistant CMLs, acute myeloid leukemia (AML), and acute megakaryoblastic leukemia (AMKL).
  • the JAK-mediated condition, disorder, or disease is a lymphoproliferative disease, including, but not limited to, myeloma.
  • the JAK-mediated condition, disorder, or disease is cancer, including, but not limited to, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer, and renal carcinoma.
  • the JAK-mediated condition, disorder, or disease is a inflammatory disease or disorder, including, but not limited to, immune dysfunction, immunodeficiency, immunomodulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).
  • a inflammatory disease or disorder including, but not limited to, immune dysfunction, immunodeficiency, immunomodulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, multiple sclerosis, thyroidit
  • the proliferative disease or the JAK-mediated condition, disorder, or disease is selected from myeloproliferative disorders, including, but not limited to, polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF), and hypereosinophilic syndrome (HES); leukemia, including, but not limited to, myeloid leukemia, chronic myeloid leukemia (CML), imatinib-resistant CMLs, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and acute
  • myeloproliferative disorders including, but not limited to, polycythemia vera (PCV), essential thrombocythemia, idiopathic myelofibrosis (IMF), and hypereosinophilic syndrome (HES); leukemia, including, but not limited to, myeloid leukemia, chronic myeloid leukemia (CML), imatinib-resistant CML
  • megakaryoblastic leukemia AKL
  • lymphoproliferative diseases including, but not limited to, myeloma
  • cancer including, but not limited to, head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain cancer, pancreatic cancer, gastric cancer, thyroid cancer, renal carcinoma, Kaposi's sarcoma, Castleman's disease, and melanoma.
  • the inflammatory disease or the JAK-mediated condition, disorder, or disease is selected from, but not limited to diseases relating to immune dysfunction, immunodeficiency or immunomodulation, including but not limited to tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease, diabetic neuropathy, autoimmune diseases, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, atopic dermatitis, myasthenia gravis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), conjunctivitis, dry eye syndrome (or keratoconjunctivitis sicca (KCS)), uveitis, ulceris, scleritis, rhinitis, sinus
  • the renal disease or the JAK-mediated condition, disorder, or disease includes diabetic neuropathy.
  • JAK-mediated diseases and disorders include, but are not limited to, restenosis, fibrosis, and scleroderma.
  • JAK-mediated diseases include, but are not limited to, viral diseases such as Epstein Barr virus (EBV), hepatitis (hepatitis B or hepatitis C), human immunodeficiency virus (HIV), human T- lymphotropic virus type 1 (HTLV-1), varicella-zoster virus, and the human papilloma virus (HPV).
  • EBV Epstein Barr virus
  • HAV human immunodeficiency virus
  • HTLV-1 human T- lymphotropic virus type 1
  • HPV varicella-zoster virus
  • the compound of Formula I provided herein is administered to the subject in the amount ranging from about 0.01 to about 1,000 mg/kg, from about 0.1 to about 500 mg/kg, from about 0.1 to about 250 mg/kg, or from about 0.1 to about 100 mg/kg.
  • the compound of Formula I provided herein is administered to the subject in the amount ranging from about 0.01 to about 1,000 mg/kg/day, from about 0.1 to about 500 mg/kg/day, from about 0.1 to about 250 mg/kg/day, or from about 0.1 to about 100 mg/kg/day.
  • the compound of Formula I provided herein is administered to the subject in the amount of about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 15, about 20, about 25, about 30, about 35, about 40 about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 105, about 120, about 130, about 140, about 150, about 160, about 170, about 180, about 190, about 200, about 300, about 400, about 500, about 600, about 700, about 750, about 800, about 900, or about 1,000 mg/kg/day.
  • the administered dose of the compound of Formula I provided herein can also be expressed in units other than the unit "mg/kg/day.”
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • doses for parenteral administration can be expressed as mg/m 2 /day.
  • One of ordinary skill in the art would readily know how to convert doses from mg/kg/day to mg/m 2 /day to given either the height or weight of a subject or both ⁇ See, www.fda.gov/cder/cancer/animalframe.htm).
  • a dose of 1 mg/kg/day for a 65 kg human is approximately equal to 38 mg/m 2 /day.
  • the compound of Formula I provided herein can be administered by oral, parenteral ⁇ e.g., intramuscular, intraperitoneal, intravenous, CIV, intracistemal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical ⁇ e.g., transdermal or local) routes of administration.
  • the compound of Formula I provided herein may be formulated, alone or together, in suitable dosage unit with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles, appropriate for each route of administration.
  • the compound of Formula I provided herein can be delivered as a single dose such as, e.g., a single bolus injection, or oral tablets or pills; or over time such as, e.g., continuous infusion over time or divided bolus doses over time.
  • intermittent administration of the compound of Formula I provided herein is administration for one to six days per week, administration in cycles (e.g. , daily administration for two to eight consecutive weeks, then a rest period with no administration for up to one week), or administration on alternate days.
  • Formula I provided herein is in the range of about a daily dose to about a monthly dose.
  • the administration of the compound of Formula I provided herein is once a day, twice a day, three times a day, four times a day, once every other day, twice a week, once every week, once every two weeks, once every three weeks, or once every four weeks.
  • the compound of Formula I provided herein is administered once a day.
  • the compound of Formula I provided herein is administered twice a day.
  • the compound of Formula I provided herein is administered three times a day.
  • the compound of Formula I provided herein is administered four times a day.
  • the subject is a mammal. In certain embodiments, the mammal is a human.
  • the proliferative disease is a tumor. In another embodiment, the proliferative disease is a solid tumor. In certain embodiments, the solid tumor is an advanced solid tumor. In certain embodiments, the solid tumor is a metastatic solid tumor. In yet another embodiment, the proliferative disease is cancer. In yet another embodiment, the proliferative disease is advanced cancer. In certain embodiments, the solid tumor is metastatic cancer.
  • the cancer treatable with the methods provided herein includes, but is not limited to, (1) leukemias, including, but not limited to, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemias such as myeloblastic,
  • CMML chronic myelomonocytic leukemia
  • lymphomas including, but not limited to, Hodgkin's disease and non-Hodgkin's disease
  • multiple myelomas including, but not limited to, smoldering multiple mye
  • choriocarcinoma (yolk-sac tumor); (32) prostate cancer, including, but not limited to, adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penal cancer; (34) oral cancer, including, but not limited to, squamous cell carcinoma; (35) basal cancer; (36) salivary gland cancer, including, but not limited to, adenocarcinoma, mucoepidermoid carcinoma, and adenoidcystic carcinoma; (37) pharynx cancer, including, but not limited to, squamous cell cancer and verrucous; (38) skin cancer, including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma, superficial spreading melanoma, nodular melanoma, lentigo malignant melanoma, and acral lentiginous melanoma; (39) kidney cancer, including, but not limited to, renal cell cancer
  • bladder cancer including, but not limited to, transitional cell carcinoma, squamous cell cancer, adenocarcinoma, and carcinosarcoma; and other cancer, including, not limited to, myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangio- endotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinomas (See Fishman et ah, 1985, Medicine, 2d Ed., J.B. Lippincott Co., Philadelphia and Murphy et ah, 1997, Informed Decisions: The Complete Book of Cancer
  • the cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, lung cancer (e.g., small cell and non- small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (e.g., osteosarcoma), skin cancer (e.g., squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
  • bladder cancer e.g., breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glio
  • the cancer that is treatable with the methods provided herein includes, but is not limited to, bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g.,
  • glioblastoma head and neck cancer
  • liver cancer non-small cell lung cancer
  • ovarian cancer pancreatic cancer
  • prostate cancer prostate cancer
  • the cancer is head and neck cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is lung adenocarcinoma. In certain embodiments, the cancer is esophogeal or upper GI cancer.
  • the subject to be treated with one of the methods provided herein has not been treated with anticancer therapy. In certain embodiments, the subject to be treated with one of the methods provided herein has been treated with anticancer therapy.
  • the methods provided herein encompass treating a subject regardless of patient's age, although some diseases or disorders are more common in certain age groups. Further provided herein is a method for treating a subject who has undergone surgery in an attempt to treat the disease or condition at issue, as well as the one who have not. Because the subjects with cancer have heterogeneous clinical manifestations and varying clinical outcomes, the treatment given to a particular subject may vary, depending on his/her prognosis.
  • Formula I is combined or used in combination with a second therapeutic agent.
  • the term “in combination” includes the use of more than one therapy (e.g. , one or more prophylactic and/or therapeutic agents). However, the use of the term “in combination” does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject with a condition, disorder, or disease.
  • a first therapy e.g.
  • a prophylactic or therapeutic agent such as a compound provided herein
  • a prophylactic or therapeutic agent can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g. , 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g. , a prophylactic or therapeutic agent) to the subject.
  • a second therapy e.g. , a prophylactic or therapeutic agent
  • Triple therapy is also contemplated herein.
  • the term "synergistic” includes a combination of the compound of Formula I provided herein and another therapy (e.g. , a prophylactic or therapeutic agent) which has been or is currently being used to prevent, treat, or manage a condition, disorder, or disease, which is more effective than the additive effects of the therapies.
  • a synergistic effect of a combination of therapies permits the use of lower dosages of one or more of the therapies and/or less frequent administration of said therapies to a subject with a condition, disorder, or disease.
  • a therapy e.g., a prophylactic or therapeutic agent
  • a synergistic effect can result in improved efficacy of agents in the prevention, treatment, or management of a condition, disorder, or disease.
  • a synergistic effect of a combination of therapies may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.
  • the compound of Formula I provided herein can be administered in combination or alternation with another therapeutic agent,.
  • combination therapy effective dosages of two or more agents are administered together, whereas in alternation or sequential-step therapy, an effective dosage of each agent is administered serially or sequentially.
  • the dosages given will depend on absorption, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens and schedules should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the second therapeutic agent is a chemotherapeutic agent, anti-proliferative agent, anti-inflammatory agent, immunomodulatory agent, or immunosuppressive agent.
  • the second therapeutic agent is an anticancer agent.
  • the anticancer agent is an antimetabolite, including, but not limited to, cytarabine (also known as cytosine arabinoside or Ara-C), fludarabine, 5- fluorouracil, gemcitabine, HDAC (high dose cytarabine), 6-mercaptopurine, methotrexate, and pemetrexed.
  • the anticancer agent is an antimicrotubule agent, including, but not limited to, vinca alkaloids (e.g., vinblastine, vincristine, and vinorelbine) and taxanes (e.g., paclitaxel, albumin-bound paclitaxel (ABRAXANE ® ), and docetaxel).
  • vinca alkaloids e.g., vinblastine, vincristine, and vinorelbine
  • taxanes e.g., paclitaxel, albumin-bound paclitaxel (ABRAXANE ® ), and docetaxel.
  • the anticancer agent is an alkylating agent, including, but not limited to, busulfan, carmustine, chlorambucil, cyclophosphamide, fludarabine, ifosfamide, mechlorethamine, melphalan, and nitrosoureas (e.g., bischloroethylnitrosurea, hydroxyurea, carmustine, and lomustine).
  • the anticancer agent is a platinum agent, including, but not limited to, carboplatin, CI-973, cisplatin, oxaliplatin, and satraplatin (JM-216).
  • the anticancer agent is an anthracycline, including, but not limited to, adriamycin, daunorubicin, and doxrubicin.
  • the anticancer agent is an antitumor antibiotic, including, but not limited to, adriamycin, bleomycin, daunomycin (also known as daunorubicin), doxorubicin, idarubicin, and mitomycin.
  • the anticancer agent is a topoisomerase inhibitor, including, but not limited to, camptothecins, etoposide, irinotecan, and topotecan.
  • the anticancer agent is a kinase inhibitor, including, but not limited to, erlotinib and imatinib.
  • the anticancer agent is a nucleoside, including, but not limited to, gemcitabine.
  • the anticancer agent is an anti-angiogenesis agent, including, but not limited to, SUTENT ® , sorafenib, and bevacizumab.
  • the anticancer agent is a cytotoxic agent, including, but not limited to, estramustine phosphate and prednimustine.
  • the anticancer agent is hormones or hormone agonists, antagonists, partial agonists or partial antagonists.
  • the anticancer agent is selected from the group consisting of enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, and megestrol), hydroxyurea, interferons, and oblimersen.
  • the anticancer agent is a monoclonal antibody, including, but not limited to bevacizumab and cetuximab.
  • the second therapeutic agent is an anti-inflammatory agent, including, but not limited to, methotrexate, matrix metalloproteinase inhibitors, inhibitors of pro-inflammatory cytokines ⁇ e.g., anti-TNF molecules, TNF soluble receptors, and ILl), non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandin synthase inhibitors ⁇ e.g., choline magnesium salicylate and salicylsalicyclic acid), COX-1 and/or COX -2 inhibitors, and glucocorticoid receptor agonists ⁇ e.g., corticosteroids, methylprednisone, prednisone, and cortisone).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • prostaglandin synthase inhibitors e.g., choline magnesium salicylate and salicylsalicyclic acid
  • COX-1 and/or COX -2 inhibitors glucocorticoid receptor agonists
  • the route of administration of the compound of Formula I provided herein is independent of the route of administration of a second therapy.
  • the compound of Formula I provided herein is administered orally.
  • the compound of Formula I provided herein is administered intravenously.
  • the compound of Formula I provided herein is administered orally or intravenously, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, pulmonarily, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
  • the compound of Formula I provided herein and a second therapy are administered by the same mode of administration, orally or by IV.
  • the compound of Formula I provided herein is administered by one mode of administration, e.g., orally, whereas the second agent (an anticancer agent) is administered by another mode of administration, e.g., by IV.
  • the compound or composition provided herein, or pharmaceutically acceptable salts, solvates or hydrates thereof, may be administered simultaneously with, prior to, or after administration of one or more of the above agents.
  • Other therapies or anticancer agents that may be used in combination with the compound provided herein include surgery, radiotherapy, endocrine therapy, biologic response modifiers (e.g., interferons, interleukins, and tumor necrosis factor (TNF)), hyperthermia and cryotherapy, and agents to attenuate any adverse effects (e.g., antiemetics).
  • a method of inhibiting the growth of a cell comprising contacting the cell with an effective amount of optically active (S)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the growth of a cell in a subject comprising administering to the subject an effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the cell is a mammalian cell. In certain embodiments, the mammal is a human cell. In certain embodiments, the cell is a tumor cell. In certain embodiments, the cell is mammalian tumor cell. In certain embodiments, the cell is a human tumor cell. In certain embodiments, the cell is a cancerous cell. In certain embodiments, the cell is mammalian cancerous cell. In certain embodiments, the cell is a human cancerous cell.
  • the cancerous cell that can be treated with the methods provided herein includes, but is not limited to, cells of bladder cancer, breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, lung cancer (e.g., small cell and non-small cell lung cancers), melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, sarcoma (e.g., osteosarcoma), skin cancer (e.g. , squamous cell carcinoma), stomach cancer, testicular cancer, thyroid cancer, and uterine cancer.
  • bladder cancer e.g., breast cancer, cervical cancer, colon cancer (e.g., colorectal cancer), endometrial cancer, esophageal cancer, gastric cancer, glioma (e.g
  • the cell is a cell of bladder cancer, breast cancer, cervical cancer, colon cancer (e.g. , colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • bladder cancer breast cancer, cervical cancer, colon cancer (e.g. , colorectal cancer), endometrial cancer, gastric cancer, glioma (e.g., glioblastoma), head and neck cancer, liver cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, or prostate cancer.
  • the inhibition of cell growth can be gauged by, e.g. , counting the number of cells contacted with a compound of interest, comparing the cell proliferation with otherwise identical cells not contacted with the compound, or determining the size of the tumor that encompasses the cells.
  • the number of cells, as well as the size of the cells can be readily assessed using any method known in the art (e.g., trypan blue exclusion and cell counting, measuring incorporation of 3 H-thymidine into nascent DNA in a cell).
  • a method of modulating the activity of a JAK kinase comprising contacting the JAK kinase with optically active ( ⁇ S)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • a method of inhibiting the activity of a JAK kinase comprising contacting the JAK kinase with optically active (5)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the JAK kinase is constitutively activated. In certain embodiments, the JAK kinase is mutated.
  • a method of modulating the activity of a JAK kinase in a subject comprising administering to the subject an effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • provided herein is a method of inhibiting the activity of a JAK kinase in a subject, comprising administering to the subject an effective amount of optically active (5)-(4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol or an isotopic variant thereof; or
  • the JAK kinase is constitutively activated. In certain embodiments, the JAK kinase is mutated.
  • a method of preventing, treating, or ameliorating one or more symptoms of an adenosine A3-mediated condition, disorder, or disease in a subject comprising administering the subject a therapeutically effective amount of optically active (i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • optically active i?)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol or an isotopic variant thereof; or pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
  • the adenosine A3-mediated conditions, disorders, or diseases include, but are not limited to, myeloproliferative disorders such as polycythemia vera (PCV), essential thrombocythemia and idiopathic myelofibrosis (IMF); leukemia such as myeloid leukemia including chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML), and a subtype of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases such as myeloma; cancer including head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer and renal carcinoma; and inflammatory diseases or disorders related to immune dysfunction, immunodeficiency, immunomodulation, autoimmune diseases, tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease including diabetic neuropathy, multiple myeloproliferative disorders such
  • a disease or disorder selected from myeloproliferative disorders such as polycythemia vera (PCV), essential thrombocythemia and idiopathic myelofibrosis (IMF) and hypereosinophilic syndrome (HES); leukemia such as myeloid leukemia including chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and a subtype of AML, acute megakaryoblastic leukemia (AMKL); lymphoproliferative diseases such as myeloma; cancer including head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain cancer, pancreatic cancer, gastric cancer, thyroid cancer, renal
  • a disease or disorder selected from myeloproliferative disorders such as polycythemia vera (PCV), essential thrombocythemia and idiopathic myelo
  • inflammatory diseases or disorders related to immune dysfunction, immunodeficiency or immunomodulation such as tissue transplant rejection, graft-versus-host disease, wound healing, kidney disease; autoimmune diseases such as multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, atopic dermatitis, myasthenia gravis, inflammatory bowel disease including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosis (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), inflammatory diseases of the eye including conjunctivitis, uveitis, ulceris, scleritis, inflammatory diseases of the respiratory tract including the upper respiratory tract such as rhinitis and sinusitis and inflammatory diseases of the lower repiratory tract including bronchitis; inflammatory myopathy such as
  • myocarditis other inflammatory diseases such as ischemia reperfusion injuries related to an inflammatory ischemic event such as a stroke or cardiac arrest, and other inflammatory conditions such as systemic inflammatory response syndrome (SIRS) and sepsis.
  • SIRS systemic inflammatory response syndrome
  • adenosine A 3 -mediated diseases and disorders include restenosis, fibrosis and scleroderma.
  • adenosine A 3 -mediated diseases include viral diseases such as Epstein Barr virus (EBV), hepatitis (hepatitis B or hepatitis C), human immunodeficiency virus (HIV), Human T-lymphotropic virus type 1 (HTLV-1), varicella-zoster virus and the human papilloma virus (HPV).
  • EBV Epstein Barr virus
  • HAV human immunodeficiency virus
  • HTLV-1 Human T-lymphotropic virus type 1
  • HPV varicella-zoster virus
  • the adenosine A 3 -mediated condition, disorder, or disease is a cardiovascular disease, including, but not limited to, ischaemic heart disease.
  • the adenosine A 3 -mediated condition, disorder, or disease is lung injury.
  • the adenosine A 3 -mediated condition, disorder, or disease is renal failure.
  • the adenosine A 3 -mediated condition, disorder, or disease is an eye disease, including, but not limited to, glaucoma and ocular hypertension.
  • the adenosine A 3 -mediated condition, disorder, or disease is glaucoma or ocular hypertension.
  • the compound of Formula I provided herein can also be provided as an article of manufacture using packaging materials well known to those of skill in the art. See, e.g., U.S. Pat. Nos. 5,323,907; 5,052,558; and 5,033,252.
  • packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • kits which, when used by the medical practitioner, can simplify the administration of appropriate amounts of active ingredients to a subject.
  • the kit provided herein includes containers and dosage forms of the compound of Formula I provided herein.
  • the kit includes a container comprising dosage forms of the compound of Formula I provided herein, in one or more containers.
  • Kits provided herein can further include devices that are used to administer the active ingredients. Examples of such devices include, but are not limited to, syringes, needleless injectors drip bags, patches, and inhalers. The kits provided herein can also include condoms for administration of the active ingredients.
  • Kits provided herein can further include pharmaceutically acceptable vehicles that can be used to administer one or more active ingredients.
  • the kit can comprise a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free sterile solution that is suitable for parenteral administration.
  • Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles including, but not limited to, Water for Injection USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection
  • water-miscible vehicles including, but not limited to,
  • Standard physiological, pharmacological, and biochemical procedures are available for determining biological activity of the compound of Formula I against JAK kinases, including wild type and mutant JAK kinases.
  • assays include, for example, biochemical assays such as binding assays (see, Fabian et al, Nature Biotechnology 2005, 23,329-336), radioactivity incorporation assays, as well as a variety of cell based assays.
  • Exemplary cell based assays include measurement of STAT5 phosphorylation, for example, by ELISA; or the measurement of proliferation in leukemic cell lines such as TF-1 or HEL-2, for example, by BrdU incorporation, by fluorescent staining, or by a reporter assay activated by the transcription factor STAT5.
  • Cells useful in the assays include cells with wildtype JAK such as TF-1 or mutated JAK such as the cell line HEL-2 which express a constitutively active JAK2 carrying the V617F mutation. Suitable cells include those derived through cell culture from patient samples as well as cells derived using routine molecular biology techniques, e.g., retroviral transduction, transfection, mutagenesis, etc.
  • DAIPEN l,l-bis(4-methoxyphenyl)-3 -methyl- 1 ,2-butanediamine
  • P-Phos (2,2',6,6'- tetramethoxy-4,4'-bis(di(3,5-xylyl)phosphino)-3,3'-bipyridine
  • FBS fetal bovine serum
  • enantiomer (1) refers to (5)-(4-fluorophenyl)(4-((5- methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol and enantiomer (2) refers to (R)-(4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • procedure for preparation of (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol using [(5)-P-Phos RuCl 2 (S)-DAIPEN] catalyst can be similarly used for preparing (S)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol using [(i?)-P-Phos RuCl 2 (i?)-DAIPEN] catalyst.
  • the S-enantiomer (the first eluting peak) had a retention time of 6.03 minutes with a peak area of 49.8%, and the i?-enantiomer (the second eluting peak) had a retention time of 7.16 minutes with a peak area of 50.2%.
  • Step B Preparation of (4-fluorophenyl)(4-(5-methyl-lH-pyrazol-3- ylamino)quinazolin-2-yl)methanone 1.
  • DIPEA 0.103 mL, 0.6 mmol
  • 5-methyl- lH-pyrazol-3-amine 88 mg, 0.9 mmol
  • Step C Preparation of (5)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol 3.
  • Binding reactions were assembled by combining kinase, liganded affinity beads, and test compounds in 1 x binding buffer (20 % SeaBlock, 0.17x PBS, 0.05 % Tween 20, 6 mM DTT). Test compounds were prepared as 100 x stocks in DMSO and rapidly diluted into the aqueous environment. DMSO was added to control assays lacking a test compound.
  • a selectivity score which is a quantitative measure of selectivity of a compound against a panel of enzymes, may be calculated for a compound by dividing the number of enzymes for which a compound meets a set criteria, (for example, a binding constant of 100 nM or less), by the total number of enzymes tested.
  • a kinase selectivity score, S10 is calculated for each compound by dividing the number of kinases for which a compound at a certain
  • concentration displayed inhibition of 90% or greater compared to negative control lacking inhibitors (DMSO only), divided by the number of distinct kinases tested excluding mutant variants, typically 359 or 386 kinases.
  • csTF-1 cells were derived from the human erythroleukemia cell line that was growth dependent on GM-CSF and had an intact GM-CSFR/JAK2/STAT5 pathway.
  • the cell line contained stably integrated beta-lactamase reporter gene under the control of the regulatory factor 1 (irf 1) response element recognized by the activated transcription factor STAT5.
  • csTF-1 cells (Invitrogen K1219) were washed with assay media (97% OPTIMEM/ 0.5% dialyzed FBS / 0.1 mM non-essential amino acids / 1 mM Na pyruvate / penicillin / streptomycin) and seeded in the same media at 5xl0 5 cell/mL in T150 flask.
  • Blue and green fluorescence were measured with excitation at 409 nm and emission at 460 nm (for blue) and excitation at 409 nm and emission at 530 nm (for green) using Spectra Max Gemini EM.
  • the racemate inhibited GM-CSF stimulated reporter activity with an EC 50 of 70 nM.
  • the individual enantiomers inhibited GM-CSF stimulated reporter activity with an EC 50 of 38 and 75 nM for the (5)(+) and (R)(-), respectively.
  • Ba/F3 cell lines were generated that exogenously express each of the four JAK proteins in a constitutively activated state. This is achieved by fusing the dimerization domain of the protein TEL with the kinase domain of the individual JAK proteins. When expressed, these fusion proteins dimerize, causing cross-activation of their associated kinase domains, which leads to phosphorylation of STAT5, among other STAT proteins, depending on the particular kinase.
  • Each cell line was generated by retroviral transduction of the recombinant fusion protein gene and subsequent single cell cloning of each resulting cell line.
  • Adenosine A 3 receptor also known as A3AR or ADORA3, is a G protein- coupled receptor (GPCR). Racemic (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol was tested in an adenosine A 3 receptor GTPyS binding assay in antagonist format, according to the procedure described in Jacobson et al. ,
  • Incubations at 1 ⁇ , 0.1 ⁇ , and 10 nM of the compound were carried out in duplicates at 30 °C for 30 min in an incubation buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 1 mM DTT, and 1 mM EDTA).
  • the assay was quantitated by measuring the amount of [ 35 S]GTPyS bound relative to 2-Cl-IB-MECA response.
  • the IC 50 of racemic (4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol against adenosine A 3 was determined to be 62.9 nM.
  • the PathHunter ⁇ -Arrestin assay monitors the activation of a recombinantly tagged GPCR utilizing enzyme fragment complementation with ⁇ -galactosidase ( ⁇ -Gal) as the functional reporter.
  • ⁇ -Gal enzyme fragment complementation with ⁇ -galactosidase
  • a human ADORA3 -expressing PathHunter cell line was grown according to standard procedures and maintained in selective growth media prior to assay. Cells were seeded in 384-well microplates at a density of 5000 cells per well in a total volume of 20 and were allowed to adhere and recover overnight prior to compound addition.
  • 2-Cl-IB-MECA agonist dose curves were performed the morning of profiling to determine the EC 80 value that was used for the following antagonist compound testing.
  • cells were preincubated with either (R)- or (5)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol antagonist or the racemic antagonist (5 of 5X compound added to cells for 30 min at 37 °C) followed by 2-Cl-IB-MECA agonist challenge at the EC 8 o concentration (5 of 6X EC 80 agonist incubated at 37 °C for 90 min).
  • Racemic (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol was tested in a phosphodiesterase PDE4 inhibition assay, according to the procedure described in Cortijo et al., Br. J. Pharmacol. 1993, 108, 562-568 and Nicholson et al., Trends Pharmacol. Sci. 1991, 12, 19-27. Human U937 cells were used in this assay. The final DMSO concentration in the assay was about 1%.
  • the assay was pre-incubated at 25 °C for 15 min and then incubated at 25 °C for 20 min in an incubation buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 ). The assay was quantitated by measuring the amount of
  • Racemic (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol was tested in a phosphodiesterase PDE5 inhibition assay, according to the procedure described in Hidaka and Asano, Biochem. Biophys. Acta 1976, 429, 485-497 and Nicholson et al, Trends Pharmacol. Sci. 1991, 12, 19-27. Human platelets were used in this assay. The final DMSO concentration in the assay was about 1%.
  • the assay was pre- incubated at 25 °C for 15 min and then incubated at 25 °C for 20 min in an incubation buffer (50 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 ). The assay was quantitated by measuring the amount of [ 3 H]guanosine.
  • the IC 50 of racemic (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol against phosphodiesterase PDE5 was determined to be 9.34 ⁇ .
  • Racemic (4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol was tested in a melatonin MT, GTPyS binding assay, according to the procedure described in Beresford et al., Biochem. Pharmacol. 1998, 56, 1167-1174. Human CHO-K1 cells Chinese hamster ovary were used in this assay. The final DMSO concentration in the assay was about 0.4%.
  • the assay mixture was incubated at 30 °C for 30 min in an incubation buffer (20 mM HEPES, pH 7.4, 100 mM NaCl, 10 mM MgCl 2 , 1 mM DTT, and 1 mM EDTA).
  • the assay was quantitated by measuring the amount of [ 35 S]GTPyS bound relative to 2-iodomelatonin response.
  • the IC 50 of racemic (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol against melatonin was determined to be 9.75 ⁇ .
  • Blood samples (approximately 1.0 mL) were collected after dosing at specified time points (5 min (IV only), 15, 30 min, 1, 2, 4, 6, and 24 hrs) into tubes containing K 3 EDTA. The samples collected were placed on wet ice/ice block and processed for plasma within 15 min. For each sample, plasma was separated and stored frozen at approximately -20 °C until analysis.
  • Plasma samples, calibration, and quality control standards were extracted with five volumes of acetonitrile containing an internal standard (25 ng/mL N-(5- cyclopropyl-lH-pyrazol-3-yl)-2-(difluoro(4-fluorophenyl)methyl)quinazolin-4-amine) and analyzed using LC-MS/MS (Sciex 4000 Qtrap) on a Regis RegisCell 5 ⁇ column (4.6 x 250 mm), eluting isocratically with hexane/isopropyl alcohol (85:15) at a flow rate of 1.75 mL/min over 9.5 min, and monitoring the 350/332 Da parent mass/fragment mass transition.
  • Each enantiomer' s peak area was integrated separately to quantify the R- and S-enantiomer levels, while both peaks were integrated together as a single integral to quantify the level of the racemic compound.
  • racemic (4-fluorophenyl)(4-((5-methyl-lH- pyrazol-3-yl)amino)quinazolin-2-yl)methanol hydrochloride were determined after administration of the racemic compound.
  • the pharmacokinetic properties of the two enantiomers in the racemic compound were also determined.
  • Table 3 For oral administration of the racemic compound, the racemic compound has a C max of 2.1 ⁇ , an AUCo - ⁇ of 8.52 ⁇ -hr, and a half-life (ti/ 2 ) of 1.2 hrs.
  • the S-isomer in the racemic compound has a C max of 0.49 ⁇ , an AUCo- ⁇ of 1.84 ⁇ -hr, and a t of 1.4 hrs, and the i?-isomer has a C max of 1.66 ⁇ , an AUCo - ⁇ of 6.50 ⁇ -hr, and a ti/ 2 of 1.2 hrs.
  • the racemic compound has a clearance (CI) of 37.27 mL/min/kg, a volume of distribution (Vd) of 2.88 L/kg, an AUCo- ⁇ of 1.29 ⁇ -hr, and a half-life of 0.9 hr.
  • the S-isomer in the racemic compound has an AUCo - ⁇ of 0.38 ⁇ -hr and a half-life of 0.5 hrs, while the i?-isomer has an AUCo - ⁇ of 0.88 ⁇ -hr and a half-life of
  • the S-isomer has a clearance of 40.55 mL/min/kg, a volume of distribution (Vd) of 2.10 L/kg, AUC 0- ⁇ of 1.18 ⁇ -hr, and a tm of 0.6 hrs.
  • the i?-isomer For IV administration of the i?-isomer, the i?-isomer has a clearance of 21.17 mL/min/kg, a volume of distribution (Vd) of 2.86 L/kg, AUC 0- ⁇ of 2.29 ⁇ -hr, and a ti/2 of 1.6 hrs.
  • Plasma samples, calibration, and quality control standards were extracted with five volumes of acetonitrile containing an internal standard (25 ng/mL N-(5- cyclopropyl-lH-pyrazol-3-yl)-2-(difluoro(4-fluorophenyl)methyl)quinazolin-4-amine) and analyzed using LC-MS/MS (Sciex 4000 Qtrap) on a Regis RegisCell 5 ⁇ column (4.6 x 250 mm), eluting isocratically with hexane/isopropyl alcohol (85:15) at a flow rate of 1.75 mL/min over 9.5 min, and monitoring the 350/332 Da parent mass/fragment mass transition.
  • Each enantiomer's peak area was integrated separately to quantify the R- and S-enantiomer levels, while both peaks were integrated together as a single integral to quantify the level of the racemic compound.
  • the racemic compound For IV administration of the racemic compound, the racemic compound has a clearance (CI) of 21.27 mL/min/kg, a volume of distribution (V d ) of 5.41 L/kg, and a half-life (ti/ 2 ) of 2.9 hrs.
  • the racemic compound For oral administration of the racemic compound, the racemic compound has a C max of 5.76 ⁇ and AUCo - ⁇ of 46.92 ⁇ -hr. The bioavailability of the racemic compound was calculated as > 100%, which may indicate nonlinear pharmacokinetics.
  • the S-isomer has a clearance (CI) of
  • the S-isomer has a C max of 1.89 ⁇ and AUCo - ⁇ of 9.93 ⁇ -hr.
  • the bioavailability of the S-isomer was calculated as 89%.
  • the i?-isomer has a clearance (CI) of 15.17 mL/min/kg, a volume of distribution (V d ) of 7.09 L/kg, and a half-life (ti /2 ) of 4.3 hrs.
  • the i?-isomer has a C max of 8.11 ⁇ and AUCo - ⁇ of 83.07 ⁇ -hr.
  • the compounds were incubated in duplicate with eight test compound concentrations (final DMSO concentration of 0.20%) with human liver microsomes (0.25 or 0.50 mg/rnL) and NADPH (ImM) in the presence of CYP isoform specific probe susbtrates (phenacetin, bupropion, taxol, diclofenac, mephenytoin, dextromethorphan, testosterone) at the K m for 10- 20 minutes at 37°C.
  • CYP isoform specific probe susbtrates phenacetin, bupropion, taxol, diclofenac, mephenytoin, dextromethorphan, testosterone
  • FIG. 4 shows the results of the Kaplan Meier survival analysis for (R)-(4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol compared to the racemate.
  • FIG. 5 shows the results of the Kaplan Meier survival analysis for (S)-(4-fluorophenyl)(4-((5 -methyl- lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol compared to the racemate.
  • the percent increase in life span (% ILS) for each compound relative to vehicle treated animals is shown in Table 8.
  • Phase I clinical study of racemic (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol HBr salt was performed in volunteers in a double-blind, placebo-controlled, three-part study where in part one, subjects received a single oral dose ranging from 60-750 mg/day of the racemate, where in part two, subjects received a QD dose ranging from 240 -720 mg/day of the racemate for 14 days continuously, and in one cohort of the part two study, BID dose of 360 mg of the racemate for 14 days continuously (for a total 720 mg/day), and where in part three a randomized, open-label, two-sequence, two-period, crossover food effect following a single dose was studied.
  • PK parameters were evaluated in plasma and in parts one and two, in urine, for racemic (4- fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol including chiral analysis of its R and S enantiomers.
  • PK parameters were computed from plasma concentration data: area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration (AUC 0-T ), area under the plasma concentration-time curve from time 0 to infinity (AUC 0- ⁇ ), maximum observed plasma concentration (C max ), time to reach C max (t max ), terminal elimination rate constant ( ⁇ ), terminal half-life (ti/ 2 ), apparent clearance after extravascular administration (CL/F), and apparent volume of distribution during the terminal phase after extravascular administration (Vz/F).
  • AUC 0-T area under the plasma concentration-time curve from time 0 to time of last quantifiable concentration
  • AUC 0- ⁇ area under the plasma concentration-time curve from time 0 to infinity
  • maximum observed plasma concentration C max
  • time to reach C max time to reach C max
  • t max terminal elimination rate constant
  • ti/ 2 terminal half-life
  • Vz/F apparent volume of distribution during the terminal phase after extravascular administration
  • the study was also designed to assess the safety, tolerability and pharmacodynamic effects of the single and multiple oral doses of racemic (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3- yl)amino)quinazolin-2-yl)methanol on human subjects.
  • the pharmacodynamic effects are based on measurement of STAT phosphorylation levels following ex vivo stimulation with cytokines signaling through JAK2 and JAK1. Also for part two of the study only, flow cytometry was performed to determine the prevalence of cellular subsets as identified by cell- type specific cell surface markers.
  • substrate and ketone refer to (4-fluorophenyl)(4-(5 -methyl-4H-pyrazol-3 -ylamino)quinazolin-2-yl)methanone
  • alcohol refers to (4-fluorophenyl)(4-((5-methyl-lH-pyrazol-3-yl)amino)quinazolin-2- yl)methanol.
  • the substrate can be prepared by methods known to those of skill in the art, including methods described elsewhere herein and in U.S. Pub. No. US 2010/0317659, the disclosure of which is incorporated herein by reference in its entirety.
  • KOtBu in tBuOH (20 %) at S/C 100/1 and 30 bar H 2 was conducted as follows: in BIOTAGE ENDEAVORTM, 3 mL of solvent, 87 mg substrate (0.25 mmol) 1 mol % catalyst (0.0025 mmol) and 1 M KOtBu in tBuOH (20%) were heated for 18 hrs at 65 °C. The % conversion and %ee were determined by HPLC. Results are presented in Table 19.
  • DAIPEN a screen of temperature, pressure and base concentration was undertaken at catalyst load S/C 100/1 in IPA with 5-100 % IM KOtBu in tBuOH, 50-65 °C and 10-30 bar H 2 was conducted as follows: in BIOTAGE ENDEAVORTM, 3 mL of solvent, 87 mg substrate (0.25 mmol) 1 mol % catalyst (0.0025 mmol) and 5-100 % IM KOtBu in tBuOH were heated for 18 hrs at 65 °C. The % conversion and %ee were determined by HPLC. Results are presented in Table 21.
  • 4H-pyrazol-3-ylamino)quinazolin-2-yl)methanone was conducted with a heterogeneous Pd/C catalyst to operate under transfer hydrogenation conditions.
  • Table 41 below provides data for conditions screening, (i?)-PPhos RuCl 2 (R)- DAIPEN or (S)-PPhos RuCl 2 (S)-DAIPEN pre-catalyst.
  • reaction conditions using DMSO (10% v/v) as co-solvent were used as the benefits in reaction rate were demonstrated previously.
  • the 600 mL Parr vessel was equipped with an intermig impeller for efficient stirring.
  • ketone refers to (4-fluorophenyl)(4-(5-methyl-lH-pyrazol-3- ylamino)quinazolin-2-yl)methanone and alcohol refers to (i?)-(4-fluorophenyl)(4-((5-methyl- lH-pyrazol-3-yl)amino)quinazolin-2-yl)methanol or (S)-(4-fluorophenyl)(4-((5-methyl- ⁇ H- pyrazol-3-yl)amino)quinazolin-2-yl)methanol.
  • BIOTAGE ENDEAVORTM reactor 3.33 mmol scale
  • An BIOTAGE ENDEAVORTM vial was charged with substrate (1.113 g, 3.33 mmol).
  • IPA 1 mL
  • DMSO 0.5 mL
  • water 0.5 mmol
  • BIOTAGE ENDEAVORTM reactor and the reaction mixture was purged with nitrogen (5 x) and hydrogen (5 x). Reaction mixture was stirred for 16 hrs at 4-5 bar (see Table 54) and 70 °C. The reaction mixture was allowed to cool, depressurized and the contents of the reaction vial were transferred to a 100 mL Erlenmeyer flask using 70 mL THF. This typically resulted in clear yellow solution. In some cases, an orange solution with undissolved solid was obtained, which indicated low/incomplete conversion. A sample was taken and reaction conversion and ee were determined by HPLC. Results are provided in Table 54. Substrates used in this experiment were obtained as described in Example 25, Table 51.
  • reaction mixture was cooled down, depressurized and the contents of reactor were transferred to a 100 mL Erlenmeyer flask containing 30 mL water. Precipitate was filtered off, washed with IP A/water (15 mL, 9/1) and dried in vacuo giving the corresponding alcohol. A sample was prepared and reaction conversion and ee were determined by HPLC. Results are provided in Table 55 below. Substrates used in this experiment were obtained as described in Example 25, Table 51.
  • a Parr autoclave was charged with substrate (3.34 g, 10 mmol) and closed. Through the injection port, IPA (7 mL), DMSO (14 mL) and water (2 mL) were added successively (the autoclave was purged with nitrogen at least five times). 7 mL of catalyst solution prepared by dissolving [(S)-PPhos RuCl 2 (5)-DAIPEN] or [(i?)-PPhos RuCl 2 (R)- DAIPEN] (5.4 mg, 0.005 mmol) in IPA (13 mL) and adding solution of t-BuOK in t-BuOH (1 mL for 5mol%) was added. The reactor was purged with nitrogen (5 x) and hydrogen (5 x).
  • reaction mixture was stirred for 16 hrs at 4 bar and 70 °C.
  • the reaction mixture was allowed to cool and depressurized.
  • a sample was taken and reaction conversion and ee were determined by HPLC.
  • the contents of the reactor were added drop wise under vigorous stirring to a 100 mL Erlenmeyer flask containing 30 mL water. Thick white precipitate formed immediately. The precipitate was filtered off, washed with water (15 mL) and dried in vacuum giving the corresponding alcohol. Results are provided in Table 55 below, ubstrates used in this experiment were obtained as described in Example 25, Table 51.
  • Tables 56 and 57 below summarize the procedures and results.
  • i?-enantiomer refers to (i?)-(4-fluorophenyl)(4-(5-methyl- lH-pyrazol-3-ylamino)quinazolin-2-yl)methanol
  • S-enantiomer refers to ( ⁇ S)-(4- fluorophenyl)(4-(5-methyl-lH-pyrazol-3-ylamino)quinazolin-2-yl)methanol.

Abstract

La présente invention concerne une pyrazolylaminoquinazoline optiquement active et ses compositions pharmaceutiques. La présente invention concerne également une méthode de traitement, de prévention ou d'amélioration d'un ou plusieurs symptômes d'un état, trouble ou maladie à médiation par JAK. La présente invention concerne en outre une méthode de traitement, de prévention ou d'amélioration d'un ou plusieurs symptômes d'une maladie proliférative, d'une maladie inflammatoire ou d'une maladie rénale.
PCT/US2011/049895 2010-09-01 2011-08-31 Pyrazolylaminoquinazoline optiquement active, et ses compositions pharmaceutiques et méthodes d'utilisation WO2012030913A1 (fr)

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JP2013527248A JP5932794B2 (ja) 2010-09-01 2011-08-31 光学活性のあるピラゾリルアミノキナゾリン及びその医薬組成物及び使用方法
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130600A1 (fr) * 2012-02-29 2013-09-06 Ambit Biosciences Corporation Formes solides comprenant de la pyrazolylaminoquinazoline optiquement active, compositions à base de celles-ci et leurs utilisations

Families Citing this family (6)

* Cited by examiner, † Cited by third party
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EP2611792B1 (fr) * 2010-09-01 2017-02-01 Ambit Biosciences Corporation Sels hydrobromiques d'une pyrazolylaminoquinazoline
ES2581840T3 (es) * 2010-09-01 2016-09-07 Ambit Biosciences Corporation Pirazolilaminoquinazolina ópticamente activa y composiciones farmacéuticas y métodos de uso de la misma
LT3179991T (lt) 2014-08-11 2021-11-10 Acerta Pharma B.V. Terapiniai btk inhibitoriaus ir bcl-2 inhibitoriaus deriniai
WO2016024232A1 (fr) 2014-08-11 2016-02-18 Acerta Pharma B.V. Combinaisons thérapeutiques d'un inhibiteur de la btk, d'un inhibiteur de la pi3k, d'un inhibiteur de la jak-2 et/ou d'un inhibiteur de la cdk 4/6
LT3179992T (lt) 2014-08-11 2022-06-27 Acerta Pharma B.V. Btk inhibitoriaus, pd-1 inhibitoriaus ir (arba) pd-l1 inhibitoriaus terapiniai deriniai
WO2024032527A1 (fr) * 2022-08-08 2024-02-15 石药集团中奇制药技术（石家庄）有限公司 Utilisation d'un composé contenant un hétéroaryle tricyclique

Citations (75)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US5612059A (en) 1988-08-30 1997-03-18 Pfizer Inc. Use of asymmetric membranes in delivery devices
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5798119A (en) 1995-06-13 1998-08-25 S. C. Johnson & Son, Inc. Osmotic-delivery devices having vapor-permeable coatings
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US5958458A (en) 1994-06-15 1999-09-28 Dumex-Alpharma A/S Pharmaceutical multiple unit particulate formulation in the form of coated cores
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6270798B2 (en) 1996-11-23 2001-08-07 Lts Lohmann Therapie-Systeme Ag Lozenge for the modified releasing of active substances in the gastrointestinal tract
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US6350458B1 (en) 1998-02-10 2002-02-26 Generex Pharmaceuticals Incorporated Mixed micellar drug deliver system and method of preparation
WO2002017918A2 (fr) 2000-08-30 2002-03-07 Pfizer Products Inc. Formulations a liberation prolongee pour les secretagogues de l'hormone de croissance
US6375987B1 (en) 1996-10-01 2002-04-23 Gattefossé, S.A. Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6623756B1 (en) 2000-04-27 2003-09-23 Noveon Ip Holdings Corp. Directly compressed solid dosage articles
WO2004015142A1 (fr) 2002-08-07 2004-02-19 Ambit Biosciences Corporation Decouplage de propagation d'insertion adn et expression de proteine a des fins d'expression phagique
US6793936B2 (en) 1998-11-02 2004-09-21 Elan Corporation, Plc Multiparticulate modified release composition
US6827947B2 (en) 2001-12-19 2004-12-07 Astrazeneca Ab Film coating
US20050038023A1 (en) * 2000-12-21 2005-02-17 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
US6958161B2 (en) 2002-04-12 2005-10-25 F H Faulding & Co Limited Modified release coated drug preparation
US7169410B1 (en) 1998-05-19 2007-01-30 Sdg, Inc. Targeted liposomal drug delivery system
US7255876B2 (en) 2001-07-27 2007-08-14 Astellas Pharma, Inc. Composition comprises sustained-release fine particles and manufacturing method thereof
WO2008005310A2 (fr) 2006-06-30 2008-01-10 Ambit Biosciences Corp. Étiquette d'acide nucléique détectable
US7416738B2 (en) 2001-09-28 2008-08-26 Mcneil-Ppc, Inc. Modified release dosage form
US7427414B2 (en) 2006-01-18 2008-09-23 Astron Research Limited Modified release oral dosage form using co-polymer of polyvinyl acetate
US20080269490A1 (en) 2005-02-18 2008-10-30 The Hong Kong Polytechnic University Method for Asymmetric Hydrosilylation of Ketones
US7485322B2 (en) 2002-12-24 2009-02-03 Lek Pharmaceuticals D.D. Modified release pharmaceutical composition
WO2010099379A1 (fr) * 2009-02-27 2010-09-02 Ambit Biosciences Corporation Dérivés de quinazoline modulant les jak kinases et leurs procédés d'utilisation

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AR038117A1 (es) * 2002-01-14 2004-12-29 Upjohn Co Agentes antivirales derivados de la 4- oxo-4,7 -dihidrofuro [2,3-b]piridin-5-carboxamida
GB0211019D0 (en) * 2002-05-14 2002-06-26 Syngenta Ltd Novel compounds
US7432275B2 (en) * 2002-12-13 2008-10-07 Neurogen Corporation Carboxylic acid, phosphate or phosphonate substituted quinazolin-4-ylamine analogues as capsaicin receptor modulators
US20080280855A1 (en) * 2005-06-22 2008-11-13 Nycomed Gmbh Process For the Production of Intermediates For the Preparation of Tricyclic Benzimidazoles
WO2008077560A1 (fr) * 2006-12-22 2008-07-03 Lonza Ag Procédé de préparation de 2-amino-1-phényléthanols optiquement actifs
BRPI0808772A2 (pt) * 2007-03-14 2014-08-12 Exelixis Inc Inibidores da via de hedgehog
MX2010002336A (es) * 2007-08-28 2010-03-25 Irm Llc Derivados de 2-bifenil-amino-4-amino-pirimidina como inhibidores de cinasa.
CA2714573A1 (fr) * 2008-02-29 2009-09-03 Pfizer Inc. Derives d'indazole
MY154000A (en) * 2008-09-22 2015-04-30 Cayman Chem Co Multiheteroaryl compounds as inhibitors of h-pgds and their use for treating prostaglandin d2 mediated diseases
ES2581840T3 (es) * 2010-09-01 2016-09-07 Ambit Biosciences Corporation Pirazolilaminoquinazolina ópticamente activa y composiciones farmacéuticas y métodos de uso de la misma

Patent Citations (80)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3536809A (en) 1969-02-17 1970-10-27 Alza Corp Medication method
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3845770A (en) 1972-06-05 1974-11-05 Alza Corp Osmatic dispensing device for releasing beneficial agent
US3916899A (en) 1973-04-25 1975-11-04 Alza Corp Osmotic dispensing device with maximum and minimum sizes for the passageway
US4008719A (en) 1976-02-02 1977-02-22 Alza Corporation Osmotic system having laminar arrangement for programming delivery of active agent
US4328245A (en) 1981-02-13 1982-05-04 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4410545A (en) 1981-02-13 1983-10-18 Syntex (U.S.A.) Inc. Carbonate diester solutions of PGE-type compounds
US4409239A (en) 1982-01-21 1983-10-11 Syntex (U.S.A.) Inc. Propylene glycol diester solutions of PGE-type compounds
US5739108A (en) 1984-10-04 1998-04-14 Monsanto Company Prolonged release of biologically active polypeptides
US5354556A (en) 1984-10-30 1994-10-11 Elan Corporation, Plc Controlled release powder and process for its preparation
US5033252A (en) 1987-12-23 1991-07-23 Entravision, Inc. Method of packaging and sterilizing a pharmaceutical product
US5052558A (en) 1987-12-23 1991-10-01 Entravision, Inc. Packaged pharmaceutical product
US5073543A (en) 1988-07-21 1991-12-17 G. D. Searle & Co. Controlled release formulations of trophic factors in ganglioside-lipsome vehicle
US5698220A (en) 1988-08-30 1997-12-16 Pfizer Inc. Asymmetric membranes in delivery devices
US5612059A (en) 1988-08-30 1997-03-18 Pfizer Inc. Use of asymmetric membranes in delivery devices
US5059595A (en) 1989-03-22 1991-10-22 Bioresearch, S.P.A. Pharmaceutical compositions containing 5-methyltetrahydrofolic acid, 5-formyltetrahydrofolic acid and their pharmaceutically acceptable salts in controlled-release form active in the therapy of organic mental disturbances
US5639480A (en) 1989-07-07 1997-06-17 Sandoz Ltd. Sustained release formulations of water soluble peptides
US5120548A (en) 1989-11-07 1992-06-09 Merck & Co., Inc. Swelling modulated polymeric drug delivery device
US6071495A (en) 1989-12-22 2000-06-06 Imarx Pharmaceutical Corp. Targeted gas and gaseous precursor-filled liposomes
US5900252A (en) 1990-04-17 1999-05-04 Eurand International S.P.A. Method for targeted and controlled release of drugs in the intestinal tract and more particularly in the colon
US5733566A (en) 1990-05-15 1998-03-31 Alkermes Controlled Therapeutics Inc. Ii Controlled release of antiparasitic agents in animals
US5840674A (en) 1990-11-01 1998-11-24 Oregon Health Sciences University Covalent microparticle-drug conjugates for biological targeting
US5639476A (en) 1992-01-27 1997-06-17 Euro-Celtique, S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
US5323907A (en) 1992-06-23 1994-06-28 Multi-Comp, Inc. Child resistant package assembly for dispensing pharmaceutical medications
US5972891A (en) 1992-12-07 1999-10-26 Takeda Chemical Industries, Ltd. Sustained-release preparation
US5591767A (en) 1993-01-25 1997-01-07 Pharmetrix Corporation Liquid reservoir transdermal patch for the administration of ketorolac
US6274552B1 (en) 1993-03-18 2001-08-14 Cytimmune Sciences, Inc. Composition and method for delivery of biologically-active factors
US5709874A (en) 1993-04-14 1998-01-20 Emory University Device for local drug delivery and methods for using the same
US5985307A (en) 1993-04-14 1999-11-16 Emory University Device and method for non-occlusive localized drug delivery
US6087324A (en) 1993-06-24 2000-07-11 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6376461B1 (en) 1993-06-24 2002-04-23 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6004534A (en) 1993-07-23 1999-12-21 Massachusetts Institute Of Technology Targeted polymerized liposomes for improved drug delivery
US5958458A (en) 1994-06-15 1999-09-28 Dumex-Alpharma A/S Pharmaceutical multiple unit particulate formulation in the form of coated cores
US5674533A (en) 1994-07-07 1997-10-07 Recordati, S.A., Chemical And Pharmaceutical Company Pharmaceutical composition for the controlled release of moguisteine in a liquid suspension
US5759542A (en) 1994-08-05 1998-06-02 New England Deaconess Hospital Corporation Compositions and methods for the delivery of drugs by platelets for the treatment of cardiovascular and other diseases
US5972366A (en) 1994-11-28 1999-10-26 The Unites States Of America As Represented By The Secretary Of The Army Drug releasing surgical implant or dressing material
US6316652B1 (en) 1995-06-06 2001-11-13 Kosta Steliou Drug mitochondrial targeting agents
US5798119A (en) 1995-06-13 1998-08-25 S. C. Johnson & Son, Inc. Osmotic-delivery devices having vapor-permeable coatings
US6267981B1 (en) 1995-06-27 2001-07-31 Takeda Chemical Industries, Ltd. Method of producing sustained-release preparation
US6045830A (en) 1995-09-04 2000-04-04 Takeda Chemical Industries, Ltd. Method of production of sustained-release preparation
US5993855A (en) 1995-09-18 1999-11-30 Shiseido Company, Ltd. Delayed drug-releasing microspheres
US6039975A (en) 1995-10-17 2000-03-21 Hoffman-La Roche Inc. Colon targeted delivery system
US5980945A (en) 1996-01-16 1999-11-09 Societe De Conseils De Recherches Et D'applications Scientifique S.A. Sustained release drug formulations
US6253872B1 (en) 1996-05-29 2001-07-03 Gmundner Fertigteile Gesellschaft M.B.H & Co., Kg Track soundproofing arrangement
US6264970B1 (en) 1996-06-26 2001-07-24 Takeda Chemical Industries, Ltd. Sustained-release preparation
US6419961B1 (en) 1996-08-29 2002-07-16 Takeda Chemical Industries, Ltd. Sustained release microcapsules of a bioactive substance and a biodegradable polymer
US6375987B1 (en) 1996-10-01 2002-04-23 Gattefossé, S.A. Process for the manufacture of pharmaceutical composition with modified release of active principle comprising the matrix
US6139865A (en) 1996-10-01 2000-10-31 Eurand America, Inc. Taste-masked microcapsule compositions and methods of manufacture
US5922356A (en) 1996-10-09 1999-07-13 Sumitomo Pharmaceuticals Company, Limited Sustained release formulation
US6113943A (en) 1996-10-31 2000-09-05 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6699500B2 (en) 1996-10-31 2004-03-02 Takeda Chemical Industries, Ltd. Sustained-release preparation capable of releasing a physiologically active substance
US6270798B2 (en) 1996-11-23 2001-08-07 Lts Lohmann Therapie-Systeme Ag Lozenge for the modified releasing of active substances in the gastrointestinal tract
US6197350B1 (en) 1996-12-20 2001-03-06 Takeda Chemical Industries, Ltd. Method of producing a sustained-release preparation
US5891474A (en) 1997-01-29 1999-04-06 Poli Industria Chimica, S.P.A. Time-specific controlled release dosage formulations and method of preparing same
US6120751A (en) 1997-03-21 2000-09-19 Imarx Pharmaceutical Corp. Charged lipids and uses for the same
US6060082A (en) 1997-04-18 2000-05-09 Massachusetts Institute Of Technology Polymerized liposomes targeted to M cells and useful for oral or mucosal drug delivery
US6350458B1 (en) 1998-02-10 2002-02-26 Generex Pharmaceuticals Incorporated Mixed micellar drug deliver system and method of preparation
US6613358B2 (en) 1998-03-18 2003-09-02 Theodore W. Randolph Sustained-release composition including amorphous polymer
US6048736A (en) 1998-04-29 2000-04-11 Kosak; Kenneth M. Cyclodextrin polymers for carrying and releasing drugs
US6589548B1 (en) 1998-05-16 2003-07-08 Mogam Biotechnology Research Institute Controlled drug delivery system using the conjugation of drug to biodegradable polyester
US7169410B1 (en) 1998-05-19 2007-01-30 Sdg, Inc. Targeted liposomal drug delivery system
US6131570A (en) 1998-06-30 2000-10-17 Aradigm Corporation Temperature controlling device for aerosol drug delivery
US6902742B2 (en) 1998-11-02 2005-06-07 Elan Corporation, Plc Multiparticulate modified release composition
US6793936B2 (en) 1998-11-02 2004-09-21 Elan Corporation, Plc Multiparticulate modified release composition
US6271359B1 (en) 1999-04-14 2001-08-07 Musc Foundation For Research Development Tissue-specific and pathogen-specific toxic agents and ribozymes
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
US6623756B1 (en) 2000-04-27 2003-09-23 Noveon Ip Holdings Corp. Directly compressed solid dosage articles
WO2002017918A2 (fr) 2000-08-30 2002-03-07 Pfizer Products Inc. Formulations a liberation prolongee pour les secretagogues de l'hormone de croissance
US20050038023A1 (en) * 2000-12-21 2005-02-17 David Bebbington Pyrazole compounds useful as protein kinase inhibitors
US7255876B2 (en) 2001-07-27 2007-08-14 Astellas Pharma, Inc. Composition comprises sustained-release fine particles and manufacturing method thereof
US7416738B2 (en) 2001-09-28 2008-08-26 Mcneil-Ppc, Inc. Modified release dosage form
US6827947B2 (en) 2001-12-19 2004-12-07 Astrazeneca Ab Film coating
US6958161B2 (en) 2002-04-12 2005-10-25 F H Faulding & Co Limited Modified release coated drug preparation
WO2004015142A1 (fr) 2002-08-07 2004-02-19 Ambit Biosciences Corporation Decouplage de propagation d'insertion adn et expression de proteine a des fins d'expression phagique
US7485322B2 (en) 2002-12-24 2009-02-03 Lek Pharmaceuticals D.D. Modified release pharmaceutical composition
US20080269490A1 (en) 2005-02-18 2008-10-30 The Hong Kong Polytechnic University Method for Asymmetric Hydrosilylation of Ketones
US7427414B2 (en) 2006-01-18 2008-09-23 Astron Research Limited Modified release oral dosage form using co-polymer of polyvinyl acetate
WO2008005310A2 (fr) 2006-06-30 2008-01-10 Ambit Biosciences Corp. Étiquette d'acide nucléique détectable
WO2010099379A1 (fr) * 2009-02-27 2010-09-02 Ambit Biosciences Corporation Dérivés de quinazoline modulant les jak kinases et leurs procédés d'utilisation
US20100317659A1 (en) 2009-02-27 2010-12-16 Sunny Abraham Jak kinase modulating compounds and methods of use thereof

Non-Patent Citations (142)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug in Drug Design, Theory and Application", 1987, APHA ACAD. PHARM. SCI.
"Design ofProdrugs", 1985, ELSEVIER
"Handbook of Pharmaceutical Additives", 2007, GOWER PUBLISHING COMPANY
"Handbook of Pharmaceutical Excipients", 2009, THE PHARMACEUTICAL PRESS AND THE AMERICAN PHARMACEUTICAL ASSOCIATION
"Modified-Release Drug Delivery Technology", 2008, MARCEL DEKKER, INC.
"Multiparticulate Oral Drug Delivery", 1994, MARCEL DEKKER
"Pharmaceutical Pelletization Technology", 1989, MARCEL DEKKER
"Pharmaceutical Preformulation and Formulation", 2009, CRC PRESS LLC: BOCA RATON
"Polymers in Drug Delivery", 2006, CRC PRESS LLC
"Remington: The Science and Practice of Pharmacy"
"Remington: The Science and Practice ofPharmacy", 2005, LIPPINCOTT WILLIAMS & WILKINS
"Remington: The Science and Practice qfPharmaqy"
ANAND ET AL., EXPERT OPIN. BIOL. THER., vol. 2, 2002, pages 607 - 620
ASGHAMEJAD ET AL.: "Transport Processes in Pharmaceutical Systems", 2000, MARCELL DEKKER, pages: 185 - 218
BADAWY ET AL., J. PHARM. SCI., vol. 9, 2007, pages 948 - 959
BALANT ET AL., EUR. J. DRUG METAB. PHARMACOKINET., vol. 15, 1990, pages 143 - 153
BALIMANE, SINKO, ADV. DRUG DELIVERY REV., vol. 39, 1999, pages 183 - 209
BARTON ET AL., MOL. CANC. THER., vol. 3, 2004, pages 11 - 20
BAXTER ET AL., LANCET, vol. 365, 2005, pages 1054 - 1056
BERESFORD ET AL., BIOCHEM. PHARMACOL., vol. 56, 1998, pages 1167 - 1174
BIOCHEM., vol. 11, 1972, pages 942 - 944
BLUME-JENSEN ET AL., NATURE, vol. 411, 2001, pages 355 - 356
BORIE ET AL., TRANSPLANTATION, vol. 79, 2005, pages 791 - 801
BOUSQUET ET AL., ONCOGENE, vol. 24, 2005, pages 7248 - 7252
BROMBERG, J. CLIN. INVEST., vol. 109, 2002, pages 1139 - 1142
BROWNE, CLIN. NEUROPHARMACOL., vol. 20, 1997, pages 1 - 12
BUNDGAARD, ADV. DRUG DELIVERY REV., vol. 8, 1992, pages 1 - 38
BUNDGAARD, ARCH. PHARM. CHEM., vol. 86, 1979, pages 1 - 39
BUNDGAARD, CONTROLLED DRUG DELIVERY, vol. 17, 1987, pages 179 - 96
BUSSEMER ET AL., CRIT. REV. THER. DRUG CARRIER SYST., vol. 18, 2001, pages 433 - 458
CAMPBELL ET AL., BLOOD, vol. 107, 2006, pages 2098 - 2100
CHCNG ET AL., BIOCHEM. PHARMACOL., vol. 22, 1973, pages 3099 - 3108
CHO, CHEM. SOC. REV., vol. 38, 2009, pages 443
CHRZANOWSKI, AAPS PHARMSCITECH., vol. 9, 2008, pages 635 - 638
CHRZANOWSKI, AAPS PHARMSCITECH., vol. 9, 2008, pages 639 - 645
CONWAY, RECENT PAT. DRUG DELIV. FORMUL., vol. 2, 2008, pages 1 - 8
CORTIJO ET AL., BR. J. PHARMACOL., vol. 108, 1993, pages 562 - 568
CORY ET AL., TETRAHEDRON LETTERS, vol. 37, 1996, pages 5675
DAUSSMANN ET AL., ENGINEERING IN LIFE SCIENCES, vol. 6, 2006, pages 125 - 129
ERION ET AL., J. PHARMACOL. EXP. THER., vol. 312, 2005, pages 554 - 560
FABIAN ET AL., NATURE BIOTECHNOLOGY, vol. 23, 2005, pages 329 - 336
FANG ET AL., CURR. DRUG DISCOV. TECHNOL., vol. 3, 2006, pages 211 - 224
FARQUHAR ET AL., J. PHARM. SCI., vol. 72, 1983, pages 324 - 325
FISHMAN ET AL.: "Medicine", 1985, J.B. LIPPINCOTT CO.
FLEISHER ET AL., ADV. DRUG DELIVERY REV., vol. 19, 1996, pages 115 - 130
FLEISHER ET AL., METHODS ENZYMOL., vol. 112, 1985, pages 360 - 381
FREEMAN ET AL., CHEM. SOC., CHEM. COMMUN., 1991, pages 875 - 877
FRIIS, BUNDGAARD, EUR. J. PHARM. SCI., vol. 4, 1996, pages 49 - 59
GAIGNAULT ET AL., PRACT. MED. CHEM., 1996, pages 671 - 696
GALLARDO ET AL., PHARM. DEV. TECHNOL., vol. 13, 2008, pages 413 - 423
GANGWAR ET AL., DES. BIOPHARM. PROP. PRODRUGS ANALOGS, 1977, pages 409 - 421
GATELY, J. NUCL. MED., vol. 27, 1986, pages 388
GAZZANIGA ET AL., EUR. J. PHARM. BIOPHARM., vol. 68, 2008, pages 11 - 18
GOMES ET AL., MOLECULES, vol. 12, 2007, pages 2484 - 2506
GORDON, DRUG METAB. DISPOS., vol. 15, 1987, pages 589
GRIESINGER ET AL., GENES CHROMOSOMES CANCER, vol. 44, 2005, pages 329 - 333
HAN ET AL., AAPS PHARMSCI., vol. 2, 2000, pages 1 - 11
HARPER, PROGRESS IN DRUG RESEARCH, vol. 4, 1962, pages 221 - 294
HIDAKA, ASANO, BIOCHEM. BIOPHYS. ACTA, vol. 429, 1976, pages 485 - 497
HU, IDRUGS, vol. 7, 2004, pages 736 - 742
HUTTUNEN ET AL., CURR. MED. CHEM., vol. 15, 2008, pages 2346 - 2365
J. ORG. CHEM., vol. 72, 2007, pages 23A - 24A
J. ORG. CHEM., vol. 72, no. 1, 2007, pages 23A - 24A
JACOBSON ET AL., NEUROPHARMACOLOGY, vol. 36, 1997, pages 1157 - 1165
JONES ET AL., BLOOD, vol. 106, 2005, pages 2162 - 2168
KALANTZI ET AL., RECENT PAT. DRUG DELIV. FORMUL., vol. 3, 2009, pages 49 - 63
KAMBOURAKIS, ROZZELL, PHARMACHEM, vol. 5, no. 9, 2006, pages 2 - 5
KHAN AHSAN Y ET AL: "Single enantiomer drugs: should they be developed?", ESSENTIAL PSYCHOPHARMACOLOGY,, vol. 7, no. 1, 1 January 2006 (2006-01-01), pages 15 - 23, XP008127389, ISSN: 1087-495X *
KISS ET AL.: "Recent developments on JAK2 inhibitors: a patent review", EXPERT OPIN. THER. PATENTS, vol. 20, no. 4, 1 April 2010 (2010-04-01), pages 471 - 495, XP001539996, ISSN: 1354-3776, DOI: 10.1517/13543771003639436 *
KRAFZ ET AL., CHEMMEDCHEM, vol. 3, 2008, pages 20 - 53
LACRONIQUE ET AL., BLOOD, vol. 95, 2000, pages 2535 - 2540
LACRONIQUE ET AL., SCIENCE, vol. 278, 1997, pages 1309 - 1312
LEVINE ET AL., BLOOD, vol. 107, 2006, pages 4139 - 4141
LIJINSKY, FOOD COSMET. TOXICOL., vol. 20, 1982, pages 393
LIJINSKY, J. NAT. CANCER INST., vol. 69, 1982, pages 1127
MALACEA ET AL., COORDINATION CHEMISTRY REVIEWS, vol. 254, 2010, pages 729 - 752
MANGOLD, MUTATION RES., vol. 308, 1994, pages 33
MARONI ET AL., EXPERT. OPIN. DRUG DELIV., vol. 2, 2005, pages 855 - 87 1
MERCHER ET AL., BLOOD, vol. 108, 2006, pages 2770 - 2778
MILICI ET AL., ARTHRITIS RESEARCH, vol. 10, 2008, pages 1 - 9
MIZEN ET AL., PHARM. BIOTECH., vol. 11, 1998, pages 345 - 365
MODIFIED-RELEASE DRUG DELIVERY TECHNOLOGY
MOORE ET AL., ACC. CHEM. RES., vol. 40, 2007, pages 1412 - 1419
MOROZOWICH ET AL.: "Design of Biopharmaceutical Properties through Prodrugs and Analogs", 1977, APHA ACAD. PHARM. SCI.
MURPHY ET AL.: "Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery", 1997, PENGUIN BOOKS U.S.A., INC.
NAGARWAL ET AL., CURR. DRUG DELIV., vol. 5, 2008, pages 282 - 289
NATHWANI, WOOD, DRUGS, vol. 45, 1993, pages 866 - 894
NICHOLSON ET AL., TRENDS PHARMACOL. SCI., vol. 12, 1991, pages 19 - 27
NOYORI, ANGEW. CHEM. INT. ED., vol. 37, 1998, pages 1703
NOYORI, ANGEW. CHEM. INT. ED., vol. 40, 2001, pages 1
NOYORI, ORG. BIOMOL. CHEM., vol. 4, 2006, pages 393
OLAH ET AL., MOL. PHARMACOL., vol. 45, 1994, pages 978 - 982
ONISHI ET AL., MOLECULES, vol. 13, 2008, pages 2136 - 2155
OSSWALD ET AL., CHIMICA OGGI, vol. 25, 2007, pages 16 - 18
PARDANAI, LEUKEMIA, vol. 22, 2008, pages 23 - 20
PARDANANI ET AL., LEUKEMIA, vol. 21, 2007, pages 1658 - 1668
PATTERSON ET AL., CURR. PHARM. DES., vol. 9, 2003, pages 2131 - 2154
PAULETTI ET AL., ADV. DRUG. DELIVERY REV., vol. 27, 1997, pages 235 - 256
PAVAN ET AL., MOLECULES, vol. 13, 2008, pages 1035 - 1065
RANE, ONCOGENE, vol. 19, 2000, pages 5662 - 5679
RANE, REDDY, ONCOGENE, vol. 19, 2000, pages 5662 - 5679
RAO, RESONACE, 2003, pages 19 - 27
RATHBONE ET AL: "Modified-Release Drug Delivery Technology", 2005, MARCEL DEKKER
RAUTIO ET AL., AAPS J, vol. 10, 2008, pages 92 - 102
RAUTIO ET AL., NAT. REV. DRUG. DISCOV., vol. 7, 2008, pages 255 - 270
ROBINSON ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 101, 2004, pages 14527 - 14532
ROY ET AL., J. CONTROL RELEASE, vol. 134, 2009, pages 74 - 80
SAIGAL ET AL., RECENT PAT. DRUG DELIV. FORMUL., vol. 3, 2009, pages 64 - 70
SALVATORE ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 90, 1993, pages 10365 - 10369
SAMANTA ET AL., CANCER RES., vol. 66, 2006, pages 6468 - 6472
SANDROS ET AL., MOLECULES, vol. 13, 2008, pages 1156 - 1178
SANTUS, BAKER, J. CONTROLLED RELEASE, vol. 35, 1995, pages 1 - 21
SAWYERS ET AL., CELL, vol. 70, 1992, pages 901 - 910
SCHLUMMER, STOLLE, SPECIALTY CHEMICALS MAGAZINE, vol. 28, 2008, pages 48 - 49
SCHWALLER ET AL., MOL. CELL, vol. 6, 2000, pages 693 - 704
SCOTT ET AL., N. ENG. J. MED., vol. 356, 2007, pages 459 - 468
SERAFIN ET AL., MINI REV. MED. CHEM., vol. 9, 2009, pages 481 - 497
SHI ET AL., EXPERT OPIN. DRUG DELIV., vol. 2, 2005, pages 1039 - 1058
SINGH ET AL., CURR. MED. CHEM., vol. I5, 2008, pages 1802 - 1826
SINHA ET AL., PHARM. RES., vol. 18, 2001, pages 557 - 564
SINHABABU, THAKKER, ADV. DRUG DELIVERY REV., vol. 19, 1996, pages 241 - 273
SLOAN ET AL., MED. RES. REV., vol. 23, 2003, pages 763 - 793
SLOAN ET AL., PHARM. RES., vol. 23, 2006, pages 2729 - 2747
STANCZAK ET AL., PHARMACOL. REP., vol. 58, 2006, pages 599 - 613
STELLA ET AL., ADV. DRUG DELIV. REV., vol. 59, 2007, pages 677 - 694
STELLA ET AL., DRUGS, vol. 29, 1985, pages 455 - 473
TAKADA ET AL.: "Encyclopedia of Controlled Drug Delivery", vol. 2, 1999, WILEY
TAN ET AL., ADV. DRUG DELIVERY REV., vol. 39, 1999, pages 117 - 151
TAYLOR, ADV. DRUG DELIVERY REV., vol. 19, 1996, pages 131 - 148
TEFFERI, N. ENG. J. MED., vol. 356, 2007, pages 444 - 445
VALENTINO, BORCHARDT, DRUG DISCOVERY TODAY, vol. 2, 1997, pages 148 - 155
VCRMA ET AL., J. CONTROLLED RELEASE, vol. 79, 2002, pages 7 - 27
VERMA ET AL., DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 26, 2000, pages 695 - 708
WADE, CHEM. BIOL. INTERACT., vol. 117, 1999, pages 191
WALLER ET AL., BR. J. CLIN. PHARMAC., vol. 28, 1989, pages 497 - 507
WANG ET AL., CURR. PHARM. DESIGN, vol. 5, 1999, pages 265 - 287
WEMUTH ET AL.: "Drug Design: Fact or Fantasy", 1984, ACADEMIC PRESS, pages: 47 - 72
WIEBE, KNAUS, ADV. DRUG DELIVERY REV., vol. 39, 1999, pages 63 - 80
WILLS, J. AM. CHEM. SOC., vol. 127, 2005, pages 7318
WILLS, TETRA. ASYMM., vol. 10, 1999, pages 2045
ZELLO, METABOLISM, vol. 43, 1994, pages 487
ZHAO ET AL., EMBO, vol. 21, 2002, pages 2159 - 2167

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013130600A1 (fr) * 2012-02-29 2013-09-06 Ambit Biosciences Corporation Formes solides comprenant de la pyrazolylaminoquinazoline optiquement active, compositions à base de celles-ci et leurs utilisations

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